Methods and compositions for regulating bone and cartilage formation

ABSTRACT

The invention provides methods and compositions for diagnostic assays for detecting bone and cartilage formation and therapeutic methods and compositions for treating disease and disorders related to bone and cartilage formation or resorption, such as osteoporosis and bone fractions. The invention also provides therapeutic methods for diseases related to bone or cartilage formation or resorption. Methods for identifying therapeutics for such diseases are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of application Ser.No. 10/125,691, entitled “Methods and Compositions for Regulating Boneand Cartilage Formation”, filed Apr. 18, 2002, which application claimsthe benefit of U.S. Provisional Application No. 60/284,786, filed onApr. 18, 2001. The contents of both applications are specificallyincorporated by reference herein.

BACKGROUND OF THE INVENTION

[0002] Bone formation is an essential process in embryonic developmentand plays a critical role in many diseases and conditions which affectmillions of humans. For example, osteoporosis is a debilitating diseasecharacterized by excessive bone loss that affects approximately 14million Americans and costs the U.S. health care system nearly $10billion annually. In about 40 percent of women and 13 percent of menover 50, osteoporosis is the underlying cause of most hip, spine, andwrist fractures. Recent studies estimate that as much as 70 percent ofthe variation in bone density is inherited. Bone density reaches adultlevels at approximately 18-22 years of life and remains relativelystable until middle age. Loss of bone density in the elderly is theconsequence of known factors such as menopause, inadequate nutrition,specific medical conditions, and unknown factors such as a person'sgenetic constitution. Physicians have very few available drugs to treatdeclining bone density and need drugs that will promote bone formationin patients.

[0003] Bone is continuously remodeled through a coupled process of boneresorption and bone formation. During bone resorption, osteoclastsattach to the mineralized bone matrix and excavate small pits on thebone surface, releasing bone collagen and minerals in the circulation.Subsequently, cross-linked N-telopeptides are released into thebloodstream during osteoclastic activity. During bone formation,osteoblasts are recruited to the newly resorbed areas on the bone wherethey deposit new collagen. When resorption and formation are in balance,there is no net change in bone mass. After a resting phase during whichthe bone is mineralized, the remodeling cycle begins again.

[0004] In addition to bone formation, another important role forosteoprogenitor cells is in vascular calcification (see, e.g. Curr OpinNephrol Hypertens (2000) 9: 11-15). Calcification is a component ofvascular disease that usually occurs in concert with atheroma formationbut through distinct pathophysiological processes. Vessel wallosteoprogenitor cells known as calcifying vascular cells can form bonematrix proteins and calcified nodules, analogous to osteoblasticdifferentiation in bone. These cells have been isolated from the tunicamedia of bovine and human arteries, and both in-vitro tissue culturemodels and mouse models of vascular calcification have been established.Studies of the effects of diabetes mellitus, hyperlipidemia, estrogensand glucocorticoids on calcifying vascular cell function provide insightinto the relationship between common human disease states and vascularcalcification.

[0005] While endochondral bone formation has been fairly wellcharacterized from a morphological perspective, this process remainslargely undefined at a gene transcriptional level. In vitro and in vivostudies have suggested that bone morphogenetic protein-2 (BMP-2) playsan important role in bone formation, however a detailed understanding ofthe molecular mechanisms involved would be useful to identify potentialgenetic targets for controlling bone formation. Accordingly, anunderstanding of the biochemical and molecular events underlying boneformation, and in particular the identity of the gene(s) expressedduring bone and cartilage formation, would provide significantdiagnostic and therapeutic applications for the treatment of diseasesrelating to bone and cartilage formation or resorption, such asosteoporosis, bone fractures and rheumatoid arthritis.

SUMMARY OF THE INVENTION

[0006] In one embodiment, the invention provides computer-readable mediacomprising a plurality of digitally encoded values representing thelevels of expression of a plurality of genes listed in Table 1, 2, 5, 6and/or 7 during bone or cartilage formation. The computer-readablemedium may comprise values representing levels of expression of at least5 genes listed in Table 1, 2, 5, 6 and/or 7. The computer-readablemedium may comprise values representing levels of expression of CLF-1and MMP23 during bone or cartilage formation. The computer-readablemedium may comprise values representing levels of expression of aplurality of genes listed in Table 6. The computer-readable medium mayfurther comprise at least one value representing a level of expressionof at least one gene that is up-or down-regulated during bone orcartilage formation in a precursor cell. In other embodiments, thecomputer-readable medium may comprise at least one value representing alevel of expression of at least one gene that is up-or down-regulatedduring a particular stage of bone or cartilage formation. Further, thecomputer-readable medium may comprise values representing levels ofexpression of at least one of Cyr61, Col2a1, Runx2, and Ctsk during boneor cartilage formation. In certain embodiments, the computer-readablemedium may comprise values representing levels of expression of aplurality of genes listed in Table 7. In still other embodiments, thecomputer-readable medium may comprise at least one value representing alevel of expression of at least one gene that is co-regulated orfunctionally connected with a gene that is up-or down-regulated during aparticular stage of bone or cartilage formation. The values on thecomputer-readable medium may represent ratios of, or differencesbetween, a level of expression of a gene in one sample and the level ofexpression of the gene in another sample. In certain embodiments, lessthan about 50% of the values in the computer-readable medium representexpression levels of genes which are not listed in Table 1, 2, 5, 6and/or 7.

[0007] In another embodiment, the invention provides computer systems,comprising, e.g., a database comprising values representing expressionlevels of a plurality of genes listed in Table 1, 2, 5, 6 and/or 7during bone or cartilage formation; and, a processor having instructionsto, receive at least one query value representing at least one level ofexpression of at least one gene listed in Table 1, 2, 5, 6 and/or 7;and, compare the at least one query value and the at least one databasevalue. The query value may represent the level of expression of a genelisted in Table 1, 2, 5, 6 and/or 7 in a diseased cell of a subjecthaving or susceptible of having a disease selected from the groupconsisting of osteodystrophy, osteohypertrophy, osteoblastoma,osteopertrusis, osteogenesis imperfecta, osteoporosis, osteopenia,osteoma and osteoblastoma; periondontal disease; hyperparathyroidism;hypercalcemia of malignancy; Paget's disease; osteolytic lesionsproduced by bone metastasis; bone loss due to immobilization or sexhormone deficiency; bone and cartilage loss caused by an inflammatorydisease, rheumatoid arthritis, osteoarthritis and bone fractures.Further, the query value may represent the level of expression of a genelisted in Table 1, 2, 5, 6 and/or 7 in a precursor cell for which thestage of bone or cartilage formation is unknown.

[0008] The invention further provides computer programs for analyzinglevels of expression of a plurality of genes listed in Table 1, 2, 5, 6and/or 7 in a cell, the computer program being disposed on a computerreadable medium and including instructions for causing a processor to:receive query values representing levels of expression of a plurality ofgenes listed in Table 1, 2, 5, 6 and/or 7 in a query cell, and, comparethe query values with levels of expression of the plurality of geneslisted in Table 1, 2, 5, 6 and/or 7 in a reference cell.

[0009] Also provided by the invention are compositions comprising aplurality of detection agents of genes listed in Table 1, 2, 5, 6 and/or7, which detection agents are capable of detecting the expression of thegenes or the polypeptides encoded by the genes, and wherein, e.g., lessthan about 50% of the detection agents are of genes which are not listedin Table 1, 2, 5, 6 and/or 7. The composition may comprise detectionagents of CLF-1 or MMP23. Other compositions comprise detection agentsof Cyr61, Col2a1, Runx2, or Ctsk. Still other compositions comprisedetection agents of genes having expression profiles similar to Cyr61,Col2a1, Runx2, or Ctsk. The detection agents may be isolated nucleicacids that hybridize specifically to nucleic acids corresponding to thegenes, e.g., at least about 5, 10 or 100 genes of Table 6. Othercompositions comprise a plurality of antagonists of a plurality of geneslisted in Table 1, 2, 5, 6 and/or 7, e.g., antisense nucleic acids,siRNAs, ribozymes or dominant negative mutants. Yet other compositionscomprise a plurality of agonists of a plurality of genes listed in Table1, 2, 5, 6 and/or 7.

[0010] Also within the scope of the invention are solid surfaces towhich are linked a plurality of detection agents of genes which arelisted in Table 1, 2, 5, 6 and/or 7, which detection agents are capableof detecting the expression of the genes or the polypeptides encoded bythe genes, and wherein, e.g., less than about 50% of the detectionagents are not detecting genes listed in Table 1, 2, 5, 6 and/or 7. Thedetection agents may be isolated nucleic acids that hybridizespecifically to the genes. The detection agents may be covalently linkedto the solid surface.

[0011] Also provided are methods for determining the difference betweenlevels of expression of a plurality of genes in Table 1, 2, 5, 6 and/or7 in a cell and reference levels of expression of the genes, comprising,e.g., providing RNA from the cell; determining levels of RNA of aplurality of genes listed in Table 1, 2, 5, 6 and/or 7 to obtain thelevels of expression of the plurality of genes in the cell; andcomparing the levels of expression of the plurality of genes in the cellto a set of reference levels of expression of the genes, to therebydetermine the difference between levels of expression of the pluralityof genes listed in Table 1, 2, 5, 6 and/or 7 in the cell and referencelevels of expression of the genes. The set of reference levels ofexpression may include the levels of expression of the genes during boneor cartilage formation. The set of reference levels of expression mayalso include the levels of expression of the genes during a particularstage of bone or cartilage formation. The set of reference levels ofexpression may further include the levels of expression of the genes ina precursor cell. The set of reference levels of expression may furtherinclude the levels of expression of the genes during a stage of bone orcartilage formation in a precursor cell. The cell may be a cell of asubject having or susceptible of having a disease selected from thegroup consisting of osteodystrophy, osteohypertrophy, osteoblastoma,osteopertrusis, osteogenesis imperfecta, osteoporosis, osteopenia,osteoma and osteoblastoma; periondontal disease; hyperparathyroidism;hypercalcemia of malignancy; Paget's disease; osteolytic lesionsproduced by bone metastasis; bone loss due to immobilization or sexhormone deficiency; bone and cartilage loss caused by an inflammatorydisease, rheumatoid arthritis, osteoarthritis and bone fractures. Themethod may comprise incubating a nucleic acid sample derived from theRNA of the cell of the subject with nucleic acids corresponding to thegenes, under conditions wherein two complementary nucleic acidshybridize to each other. The nucleic acids corresponding to the genesmay be attached to a solid surface. The method may comprise entering thelevels of expression of the plurality of genes into a computer thatcomprises a memory with values representing the set of reference levelsof expression. Comparing the level may comprise providing to thecomputer instructions to perform.

[0012] In another embodiment, the invention provides methods fordetermining whether a subject has or is likely to develop a diseaserelated to bone or cartilage resorption, comprising, e.g., obtaining abiological sample from the subject and comparing gene expression levelsin the biological sample to those of a set of reference levels ofexpression during normal bone and cartilage formation, whereinsignificant differences in the levels of expression of the plurality ofgenes indicates that the subject has or is likely to develop a diseaserelated to bone or cartilage resorption. The disease may be selectedfrom the group consisting of osteoporosis, osteopenia, periondontaldisease; osteolytic lesions produced by bone metastasis; bone loss dueto immobilization or sex hormone deficiency; bone and cartilage losscaused by an inflammatory disease, rheumatoid arthritis andosteoarthritis.

[0013] In another embodiment, the invention provides methods fordetermining whether a subject has or is likely to develop a diseaserelated to bone or cartilage formation, comprising, e.g., obtaining abiological sample from the subject and comparing gene expression levelsin the biological sample to those of a set of reference levels ofexpression during normal bone and cartilage formation, whereinsignificant similarities in the levels of expression of the plurality ofgenes indicates that the subject has or is likely to develop a diseaserelated to bone or cartilage formation. The disease may be selected fromthe group consisting of osteodystrophy, osteohypertrophy, osteoblastoma,osteopertrusis, osteogenesis imperfecta, osteoma and osteoblastoma,hyperparathyroidism; hypercalcemia of malignancy; and Paget's disease.

[0014] In yet another embodiment, the invention provides methods fordetermining the effectiveness of a treatment intended to stimulate boneor cartilage formation, comprising, e.g., obtaining a biological samplefrom the subject and comparing gene expression levels in the biologicalsample to those of a set of reference levels of expression during normalbone and cartilage formation, wherein significant similarities in thelevels of expression of the plurality of genes indicates that thetreatment is effective. The biological sample may be obtained from thehealing region of a bone fracture and a similarity in levels ofexpression of the plurality of genes in the cell of the subject and thereference levels of expression indicates that the fracture is healing.The method may further comprise iteratively providing a biologicalsample from the subject, such as to determine an evolution of the levelsof expression of the genes in the subject. The set of reference levelsof expression may be in the form of a database. The database may beincluded in a computer-readable medium. The database may be incommunications with a microprocessor and microprocessor instructions forproviding a user interface to receive expression level data of a subjectand to compare the expression level data with the database.

[0015] The invention also provides methods for determining theeffectiveness of a treatment intended to reduce bone or cartilageformation, comprising, e.g., obtaining a biological sample from thesubject and comparing gene expression levels in the biological sample tothose of a set of reference levels of expression during normal bone andcartilage formation, wherein significant differences in the levels ofexpression of the plurality of genes indicates that the treatment iseffective.

[0016] The methods of the invention may comprise obtaining a sample;identifying expression levels of a plurality of genes listed in Table 1,2, 5, 6 and/or 7 from the sample; determining whether the levels ofexpression of the genes in the patient sample are more similar to thoseof a cell differentiating into bone or cartilage or to those of aprecursor cell; and transmitting the results. The results may betransmitted across a network.

[0017] The invention also provides methods for identifying a compoundfor treating a disease related to bone or cartilage formation,comprising, e.g., providing levels of expression of a plurality of geneslisted in Table 1, 2, 5, 6 and/or 7 in a cell of a subject incubatedwith a test compound; providing levels of expression of a celldifferentiating into bone or cartilage; and comparing the two levels ofexpression, wherein significantly different levels of expression in thetwo cells indicates that the compound is likely to be effective fortreating a disease related to bone or cartilage formation. Also providedare methods for identifying a compound for treating a disease related tobone or cartilage resorption, comprising, e.g., providing levels ofexpression of a plurality of genes listed in Table 1, 2, 5, 6 and/or 7in a cell of a subject incubated with a test compound; providing levelsof expression of a cell differentiating into bone or cartilage; andcomparing the two levels of expression, wherein significantly similarlevels of expression in the two cells indicates that the compound islikely to be effective for treating a disease related to bone orcartilage formation.

[0018] In yet another embodiment, the invention provides a method foridentifying a compound that modulates bone or cartilage formation,comprising, e.g., contacting a precursor cell with an agent thatstimulates bone or cartilage formation and a test compound; anddetermining the level of expression of one or more genes of Tables 1, 2,6 and 7 during the bone or cartilage formation; wherein a significantsimilarity or difference between the expression level of the genes inthe cell and reference expression levels of the genes during bone orcartilage formation indicates that the test compound modulates bone orcartilage formation. The reference expression levels may be essentiallyidentical to the levels set forth in Table 1, 2, 5, 6 and/or 7. Othermethods for identifying a compound that stimulates bone or cartilageformation, comprises, e.g., contacting a precursor cell with a testcompound; and determining the level of expression of one or more genesof Tables 1, 2, 6 and 7 in the cell over time; wherein a similaritybetween the expression level of the genes in the cell and referenceexpression levels of the genes during bone or cartilage formationindicates that the test compound stimulates bone or cartilage formation.The reference expression levels may be levels set forth in Table 1, 2,5, 6 and/or 7.

[0019] Also provided are methods for identifying a compound that bindsto a polypeptide encoded by a gene listed in Table 1, 2, 5, 6 and/or 7,comprising, e.g., contacting a polypeptide encoded by a gene listed inTable 1, 2, 5, 6 and/or 7 with a test compound under essentiallyphysiological conditions; and determining whether the compound binds tothe polypeptide. In another embodiment, the invention provides a methodfor identifying a compound that modulates a biological activity of apolypeptide encoded by a gene listed in Table 1, 2, 5, 6 and/or 7,comprising, e.g., contacting a polypeptide encoded by a gene listed inTable 1, 2, 5, 6 and/or 7 with a test compound under essentiallyphysiological conditions; and determining the biological activity of thepolypeptide, wherein a higher or lower biological activity of thepolypeptide in the presence of the test compound relative to the absenceof the test compound indicates that the test compound modulates thebiological activity of the polypeptide. The gene may be CLF-1 or MMP23.Other methods for identifying a compound for treating a disease relatedto bone or cartilage formation or resorption, comprise, e.g.,identifying a compound that modulates the activity of a polypeptideencoded by a gene listed in Table 1, 2, 6 or 7; and contacting aprecursor cell with the compound in the presence or absence of an agentthat stimulates the differentiation into bone or cartilage, whereinstimulation or inhibition of bone or cartilage formation from the cellindicates that the test compound is effective for treating a diseaserelated to bone or cartilage formation or resorption.

[0020] The invention also provides methods of treatment, e.g., methodsfor treating a disease related to bone or cartilage formation orresorption, comprising administering to a subject having a diseaserelated to bone or cartilage formation or resorption a compound thatmodulates the biological activity of a polypeptide encoded by a genelisted in Table 1, 2, 5, 6 and/or 7 and thereby modulates bone orcartilage formation, to thereby treat the disease in the subject.

[0021] Also within the scope of the invention are diagnostic or drugdiscovery kits, e.g., comprising a computer-readable medium, acomposition a solid surface as described herein, and optionallyinstructions for use.

BRIEF DESCRIPTION OF THE FIGURES

[0022]FIG. 1 shows a time course for BMP-2 induction of cytokinereceptor-like factor 1 expression (CLF-1) in a mouse model of ectopicbone formation.

[0023]FIG. 2 shows a time course for BMP-2 induction of matrixmetalloproteinase 23 expression (MMP23) in a mouse model of ectopic boneformation.

[0024]FIG. 3 shows time-dependent changes in the expression of selectedmarker genes of endochondral bone formation. FIG. 3A shows changes inexpression for Cyr61; FIG. 3B shows changes in expression for Col2al;FIG. 3C shows changes in expression for Runx2; and FIG. 3D shows changesin expression for Ctsk.

BRIEF DESCRIPTION OF THE TABLES

[0025] Table 1 lists genes on the U74 microarrays for which BMP-2induced at least a two-fold increase in expression at any time point.

[0026] Table 2 lists genes on the U74 microarrays for which BMP-2induced at least a two-fold decrease in expression at any time point.

[0027] Table 3 summarizes the cells stained with an antisense riboprobefor CLF-1 mRNA.

[0028] Table 4 summarizes the cells stained with an antisense riboprobefor MMP23 mRNA.

[0029] Table 5 lists genes, previously associated with bone or cartilagemetabolism, on the Mu 1a microarray for which BMP-2 induced at least afour-fold change in expression at any time point.

[0030] Table 6 lists genes, not associated with bone or cartilagemetabolism, on the Mula microarray for which BMP-2 induced at least afour-fold change in expression at any time point.

[0031] Table 7 lists genes from Tables 5 and 6 whose expression profilescorrelate with those of selected gene markers for processes contributingto bone formation.

DETAILED DESCRIPTION OF THE INVENTION

[0032] The invention is based at least in part on the identification ofgenes which are up- and down-regulated during bone and cartilageformation, in particular, during endochondral or ectopic bone formation.Genes which are modulated include cell surface proteins, cytokines,extracellular matrix proteins, extracellular proteins, intracellularproteins, proteases, receptors, signal transduction proteins andtranscription factors. In these expression profiles, certain genes aresignificantly up-regulated, e.g., MMP23, CLF-1, cadherin 11, and CD68antigen, and certain genes are significantly down-regulated, e.g.,vascular endothelial growth factor B and fatty acid synthase, duringdifferentiation. Tables 1 and 2 list genes which are modulated by afactor of at least about 2 and Tables 5 and 6 list genes which aremodulated by a factor of at least about 4. Genes of particular interestare indicated in italics and in bold in the Tables.

[0033] Whereas some of the genes listed in the Tables may have beenknown to be potentially involved in bone and cartilage formation, manyother genes listed in the Tables have never before been associated withthese processes.

[0034] One of the genes not previously known to be associated with boneor cartilage formation that was found to be significantly up-regulatedand then down-regulated during the mesenchymal cell differentiation intobone and cartilage is Cytokine Receptor-Like Factor 1 (CLF-1 or CLRF-1,as in Table 6) (see, FIG. 1). Its up-regulation during bone formation isshown in FIG. 1. The mouse CLF-1 gene (also known as CRLM3 mRNA forcytokine receptor like molecule 3) is transcribed into a 1646 bp mRNA(SEQ ID NO: 1; GenBank Accession No. AB040038) which encodes a mouseprotein of 425 amino acids (GenBank Accession No. BAA92777) and a humanprotein of 422 amino acids. The nucleotide and amino acid sequences ofhuman CLF-1 are set forth as GenBank Accession Nos. NM_(—)004750 (SEQ IDNO: 1) and NP_(—)004741 (SEQ ID NO: 2) (Elson et al. (1998) J. Immunol.161:1371. Other human nucleotide sequences have GenBank Accession Nos.AX205046 and AF073515. Other human amino acid sequences have GenBankAccession Nos. AAD39681. The protein is secreted and dimerizes withcardiotrophin-like cytokine (CLC) (Elson et al. (2000) NatureNeuroscience 3(9): 867-872). This heterodimer is also a cytokine (Elson,et al. Nature Neuroscience 3(9):867-872, 2000). The CLC/CLF-1heterodimeric cytokine binds to ciliary neurotrophic factor receptor(CNTFR) (Elson, et al. Nature Neuroscience 3(9):867-872, 2000). Ligationof CNTFR activates STAT3 (Lelievre et al., J. Biol. Chem.276(25):22476-22484, 2001). STAT3 activation is tied to thedifferentiation of a number of cell types such as osteoblasts andosteoclasts. CLF-1 plays a role in promoting the differentiation ofmesenchymal progenitor cells towards either chrondrocytes orosteoblasts.

[0035] Another gene that was not previously known to be associated withbone or cartilage formation that was found to be up- and thendown-regulated during bone and cartilage formation is MatrixMetalloproteinase 23 (MMP23) (see FIG. 2). Its upregulation during bonedevelopment is set forth in FIG. 2. The gene is transcribed into a mRNAof 1434 base pairs (GenBank Accession No. AF085742), which encodes aprotein of 391 amino acid (GenBank Accession No. AAC34886). Thenucleotide and amino acid sequences of human MMP23 have GenBankAccession No. AJ005256 (SEQ ID NO: 3) and CAB38176 (SEQ ID NO: 4)(Velasco et al. (1999) J. Biol. Chem. 274:4570. The MMP23 protein is asecreted and also membrane bound protease. Unlike other MMPs it issecreted as an active protease. MMP23 plays a role in normal tissueremodeling (which is part of the bone formation) and in pathologicalerosion of extracellular matrix proteins (which is part of an arthriticdisease).

[0036] In another aspect, the invention is based at least in part on theidentification of genes which are up- and down-regulated duringparticular phases of bone and cartilage formation. Table 7 containsgenes whose time-dependent expression profiles correlate with theprofiles of four phenotypic markers (Cyr 61, Col2a1, Runx2, and Ctsk) ofone or more phases of endochondral bone formation. Cyr61 is a member ofthe CCN family of growth factors and is believed to regulate theproliferation and differentiation of various connective tissue celltypes. Col2a1, Runx2 and Ctsk are well-defined markers for chondrocytes,osteoblasts and osteoclasts, respectively. Such genes may also bemarkers of bone formation phases, or have a functional connection to themarkers with whose expression they correlate.

[0037] Although at least some of the genes listed in Tables 1, 2, 5, 6and/or 7 may not be human genes, corresponding human genes are availableor can be obtained within undue experimentation by a person of skill inthe art. Methods of the invention may use human or non-human genes,depending on the similarity between the two and the particular use ofthe genes. A person of skill in the art can determine whether a nucleicacid or protein of a human or non-human gene can be used.

[0038] 1. Definitions:

[0039] As used herein, the following terms and phrases shall have themeanings set forth below. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood to one of ordinary skill in the art to which this inventionbelongs.

[0040] The singular forms “a,” “an,” and “the” include plural referenceunless the context clearly dictates otherwise.

[0041] The phrase “a corresponding normal cell of” or “normal cellcorresponding to” or “normal counterpart cell of” a diseased cell refersto a normal cell of the same type as that of the diseased cell.

[0042] The term “agonist,” as used herein, is meant to refer to an agentthat mimics or upregulates (e.g., potentiates or supplements) thebioactivity of a protein. An agonist can be a wild-type protein orderivative thereof having at least one bioactivity of the wild-typeprotein. An agonist can also be a compound that upregulates expressionof a gene or which increases at least one bioactivity of a protein. Anagonist can also be a compound which increases the interaction of apolypeptide with another molecule, e.g., a target peptide or nucleicacid.

[0043] “Antagonist” as used herein is meant to refer to an agent thatdownregulates (e.g., suppresses or inhibits) at least one bioactivity ofa protein. An antagonist can be a compound which inhibits or decreasesthe interaction between a protein and another molecule, e.g., a targetpeptide or enzyme substrate. An antagonist can also be a compound thatdown-regulates expression of a gene or which reduces the amount ofexpressed protein present.

[0044] By “array” or “matrix” is meant an arrangement of addressablelocations or “addresses” on a device. The locations can be arranged intwo dimensional arrays, three dimensional arrays, or other matrixformats. The number of locations can range from several to at leasthundreds of thousands. Most importantly, each location represents atotally independent reaction site. A “nucleic acid array” refers to anarray containing nucleic acid probes, such as oligonucleotides or largerportions of genes. The nucleic acid on the array is preferably singlestranded. Arrays wherein the probes are oligonucleotides are referred toas “oligonucleotide arrays” or “oligonucleotide chips.” A “microarray,”also referred to herein as a “biochip” or “biological chip” is an arrayof regions having a density of discrete regions of at least about100/cm², and preferably at least about 1000/cm². The regions in amicroarray have typical dimensions, e.g., diameters, in the range ofbetween about 10-250 μm, and are separated from other regions in thearray by about the same distance.

[0045] The term “biological sample”, as used herein, refers to a sampleobtained from a subject, e.g., a human or from components (e.g.,tissues) of a subject. The sample may be of any biological tissue orfluid. Frequently the sample will be a “clinical sample” which is asample derived from a patient. Such samples include, but are not limitedto bodily fluids which may or may not contain cells, e.g., blood,synovial fluid; tissue or fine needle biopsy samples, such as from bone,cartilage or tissues containing mesenchymal cells. Biological samplesmay also include sections of tissues such as frozen sections taken forhistological purposes.

[0046] The term “biomarker” of a disease related to bone or cartilageformation or resorption refers to a gene which is up- or down-regulatedin a diseased cell of a subject having such a disease, relative to acounterpart normal cell, which gene is sufficiently specific to thediseased cell that it can be used, optionally with other genes, toidentify or detect the disease. Generally, a biomarker is a gene that ischaracteristic of the disease.

[0047] “Bone formation” or “bone development” refers to ossification orosteogenesis, such as by endochondral bone formation or intramembraneousbone formation. In intramembraneous bone formation, osteogenesis occursdirectly in the condensed mesenchymal cells. In endochondralossification, mesenchymal cells first condense to form a cartilagemodel, and then bone formation occurs replacing the cartilage.Osteoprogenitor cells include mesenchymal and skeletal mesenchymalcells. Angiogenesis is part of bone formation. Thus, inhibiting orstimulating angiogenesis may inhibit or stimulate bone formation.

[0048] A “cell characteristic of a disease” also referred to as a“diseased cell” refers to a cell of a subject having a disease, whichcell is affected by the disease, and is therefore different from thecorresponding cell in a non-diseased subject. A diseased cell can alsobe a cell that is present in significantly higher or lower numbers in asubject having the disease relative to a healthy subject. For example acell characteristic of cancer is a cancer cell or tumor cell. A diseasedcell may also differ from a normal cell in its gene expression profile.A disease cell of a disease relating to bone or cartilage formation orresorption can be a mesenchymal cell, a chondroblast, a chondrocyte, anosteoblast, an osteocyte, a fibroblast or other cells present in bone orcartilage or in bone or cartilage forming tissues.

[0049] A “cell sample characteristic of a disease” or a “tissue samplecharacteristic of a disease” refers to a sample of cells, such as atissue, that contains at least one cell characteristic of the disease.

[0050] A “computer readable medium” is any medium that can be used tostore data which can be accessed by a computer. Exemplary media include:magnetic storage media, such as a diskettes, hard drives, and magnetictape; optical storage media such as CD-ROMs; electrical storage mediasuch as RAM and ROM; and hybrids of these media, such asmagnetic/optical storage medium.

[0051] The term “derivative” refers to the chemical modification of acompound, e.g., a polypeptide, or a polynucleotide. Chemicalmodifications of a polynucleotide can include, for example, replacementof hydrogen by an alkyl, acyl, or amino group. A derivativepolynucleotide encodes a polypeptide which retains at least onebiological or immunological function of the natural molecule. Aderivative polypeptide can be one modified by glycosylation, pegylation,or any similar process that retains at least one biological orimmunological function of the polypeptide from which it was derived.

[0052] A disease, disorder, or condition “associated with” or“characterized by” or “relating to bone or cartilage formation orresorption” refers to a disease, condition or disorder involving cellsthat are associated with bone or cartilage formation or resorption.Exemplary diseases include osteodystrophy, osteohypertrophy,osteoblastoma, osteopertrusis, osteogenesis imperfecta, osteoporosis,osteopenia, osteoma and osteoblastoma; periondontal disease;hyperparathyroidism; hypercalcemia of malignancy; Paget's disease;osteolytic lesions produced by bone metastasis; bone loss due toimmobilization or sex hormone deficiency; bone and cartilage loss causeby an inflammatory disease, e.g., rheumatoid arthritis andosteoarthritis; wound healing and related tissue repair (e.g., burns,incisions and ulcers) and bone fractures. A “disease relating to bone orcartilage formation” refers to a disease, disorder or condition that canbe treated by inhibiting bone or cartilage formation. A “diseaserelating to bone or cartilage resorption” refers to a disease, disorderor condition that can be treated by stimulating bone or cartilageformation.

[0053] A “detection agent of a gene” refers to an agent that can be usedto specifically detect a gene or other biological molecule relating toit, e.g., RNA transcribed from the gene and polypeptides encoded by thegene. Exemplary detection agents are nucleic acid probes which hybridizeto nucleic acids corresponding to the gene, polypeptide probes,polypeptides, such asantibodies, and small molecules.

[0054] The term “equivalent” is understood to include nucleotidesequences encoding functionally equivalent polypeptides. Equivalentnucleotide sequences will include sequences that differ by one or morenucleotide substitutions, additions or deletions, such as allelicvariants; and will, therefore, include sequences that differ from thenucleotide sequence of the nucleic acids referred to in Any of Tables1-5 due to the degeneracy of the genetic code.

[0055] The term “expression profile,” which is used interchangeablyherein with “gene expression profile,” “finger print” and “expressionpattern” refers to a set of values representing the activity of about 10or more genes. An expression profile preferably comprises valuesrepresenting expression levels of at least about 20 genes, preferably atleast about 30, 50, 100, 200 or more genes.

[0056] “Genes that are up- or down-regulated” in a particular process,e.g., bone and cartilage formation, refer to genes which are up- ordown-regulated by, e.g., a factor of at least about 1.1 fold, 1.25 fold,1.5 fold, 2 fold, 5 fold, 10 fold or more. Exemplary genes that are up-or down-regulated during bone and cartilage formation are set forth inTables 1, 2, 5, 6 and/or 7. “Genes that are up- or down-regulated in adisease” refer to the genes which are up- or down-regulated by, e.g., atleast about 1.1 fold, 1.25 fold, 1.5 fold, 2 fold, 5 fold, 10 fold ormore in at least about 50%, preferably 60%, 70%, 80%, or 90% of thepatients having the disease.

[0057] “Hybridization” refers to any process by which a strand ofnucleic acid binds with a complementary strand through base pairing. Twosingle-stranded nucleic acids “hybridize” when they form adouble-stranded duplex. The region of double-strandedness can includethe full-length of one or both of the single-stranded nucleic acids, orall of one single stranded nucleic acid and a subsequence of the othersingle stranded nucleic acid, or the region of double-strandedness caninclude a subsequence of each nucleic acid. Hybridization also includesthe formation of duplexes which contain certain mismatches, providedthat the two strands are still forming a double stranded helix.“Stringent hybridization conditions” refers to hybridization conditionsresulting in essentially specific hybridization.

[0058] The term “isolated” as used herein with respect to nucleic acids,such as DNA or RNA, refers to molecules separated from other DNAs, orRNAs, respectively, that are present in the natural source of themacromolecule. The term isolated as used herein also refers to a nucleicacid or peptide that is substantially free of cellular material, viralmaterial, or culture medium when produced by recombinant DNA techniques,or chemical precursors or other chemicals when chemically synthesized.Moreover, an “isolated nucleic acid” is meant to include nucleic acidfragments which are not naturally occurring as fragments and would notbe found in the natural state. The term “isolated” is also used hereinto refer to polypeptides which are isolated from other cellular proteinsand is meant to encompass both purified and recombinant polypeptides.

[0059] As used herein, the terms “label” and “detectable label” refer toa molecule capable of detection, including, but not limited to,radioactive isotopes, fluorophores, chemiluminescent moieties, enzymes,enzyme substrates, enzyme cofactors, enzyme inhibitors, dyes, metalions, ligands (e.g., biotin or haptens) and the like. The term“fluorescer” refers to a substance or a portion thereof which is capableof exhibiting fluorescence in the detectable range. Particular examplesof labels which may be used under the invention include fluorescein,rhodamine, dansyl, umbelliferone, Texas red, luminol, NADPH, alpha-beta-galactosidase and horseradish peroxidase.

[0060] The “level of expression of a gene” refers to the activity of agene, which can be indicated by the level of mRNA, as well as pre-mRNAnascent transcript(s), transcript processing intermediates, maturemRNA(s) and degradation products, and polypeptides encoded by the gene.Accordingly, the level of expression of a gene also refers to the amountof polypeptide encoded by the gene.

[0061] The phrase “normalizing expression of a gene” in a diseased cellrefers to an action to compensate for the altered expression of the genein the diseased cell, so that it is essentially expressed at the samelevel as in the corresponding non diseased cell. For example, where thegene is over-expressed in the diseased cell, normalization of itsexpression in the diseased cell refers to treating the diseased cell insuch a way that its expression becomes essentially the same as theexpression in the counterpart normal cell. “Normalization” preferablybrings the level of expression to within approximately a 50% differencein expression, more preferably to within approximately a 25%, and evenmore preferably 10% difference in expression. The required level ofcloseness in expression will depend on the particular gene, and can bedetermined as described herein. The phrase “normalizing gene expressionin a diseased cell” refers to an action to normalize the expression of asubstantial number of genes in the diseased cell.

[0062] As used herein, the term “nucleic acid” refers to polynucleotidessuch as deoxyribonucleic acid (DNA), and, where appropriate, ribonucleicacid (RNA). The term should also be understood to include, asequivalents, analogs of either RNA or DNA made from nucleotide analogs,and, as applicable to the embodiment being described, single (sense orantisense) and double-stranded polynucleotides. ESTs, chromosomes,cDNAs, mRNAs, and rRNAs are representative examples of molecules thatmay be referred to as nucleic acids.

[0063] The phrase “nucleic acid corresponding to a gene” refers to anucleic acid that can be used for detecting the gene, e.g., a nucleicacid which is capable of hybridizing specifically to the gene.

[0064] The term “percent identical” refers to sequence identity betweentwo amino acid sequences or between two nucleotide sequences. Identitycan each be determined by comparing a position in each sequence whichmay be aligned for purposes of comparison. When an equivalent positionin the compared sequences is occupied by the same base or amino acid,then the molecules are identical at that position; when the equivalentsite occupied by the same or a similar amino acid residue (e.g., similarin steric and/or electronic nature), then the molecules can be referredto as homologous (similar) at that position. Expression as a percentageof homology, similarity, or identity refers to a function of the numberof identical or similar amino acids at positions shared by the comparedsequences. Various alignment algorithms and/or programs may be used,including FASTA, BLAST, or ENTREZ. FASTA and BLAST are available as apart of the GCG sequence analysis package (University of Wisconsin,Madison, Wis.), and can be used with, e.g., default settings. ENTREZ isavailable through the National Center for Biotechnology Information,National Library of Medicine, National Institutes of Health, Bethesda,Md. In one embodiment, the percent identity of two sequences can bedetermined by the GCG program with a gap weight of 1, e.g., each aminoacid gap is weighted as if it were a single amino acid or nucleotidemismatch between the two sequences. Other techniques for alignment aredescribed in Methods in Enzymology, vol. 266: Computer Methods forMacromolecular Sequence Analysis (1996), ed. Doolittle, Academic Press,Inc., a division of Harcourt Brace & Co., San Diego, Calif., USA.Preferably, an alignment program that permits gaps in the sequence isutilized to align the sequences. The Smith-Waterman is one type ofalgorithm that permits gaps in sequence alignments. See Meth. Mol. Biol.70: 173-187 (1997). Also, the GAP program using the Needleman and Wunschalignment method can be utilized to align sequences. An alternativesearch strategy uses MPSRCH software, which runs on a MASPAR computer.MPSRCH uses a Smith-Waterman algorithm to score sequences on a massivelyparallel computer. This approach improves ability to pick up distantlyrelated matches, and is especially tolerant of small gaps and nucleotidesequence errors. Nucleic acid-encoded amino acid sequences can be usedto search both protein and DNA databases. Databases with individualsequences are described in Methods in Enzymology, ed. Doolittle, supra.Databases include Genbank, EMBL, and DNA Database of Japan (DDBJ).

[0065] “Perfectly matched” in reference to a duplex means that the poly-or oligonucleotide strands making up the duplex form a double strandedstructure with one other such that every nucleotide in each strandundergoes Watson-Crick basepairing with a nucleotide in the otherstrand. The term also comprehends the pairing of nucleoside analogs,such as deoxyinosine, nucleosides with 2-aminopurine bases, and thelike, that may be employed. A mismatch in a duplex between a targetpolynucleotide and an oligonucleotide or olynucleotide means that a pairof nucleotides in the duplex fails to undergo Watson-Crick bonding. Inreference to a triplex, the term means that the triplex consists of aperfectly matched duplex and a third strand in which every nucleotideundergoes Hoogsteen or reverse Hoogsteen association with a basepair ofthe perfectly matched duplex.

[0066] A “plurality” refers to two or more.

[0067] A “precursor cell”, or “progenitor cell”, refers to a cell thathas the capacity to create progeny that are more differentiated thanitself. For example, the term may refer to an undifferentiated cell orcell differentiated to an extent short of final differentiation which iscapable of proliferation and giving rise to more progenitor cells havingthe ability to generate a large number of mother cells that can in turngive rise to differentiated, or differentiable daughter cells. Incertain embodiments, the term progenitor cell refers to a generalizedmother cell whose descendants (progeny) specialize, often in differentdirections, by differentiation, e.g., by acquiring completely individualcharacters, as occurs in progressive diversification of embryonic cellsand tissues. Cellular differentiation is a complex process typicallyoccurring through many cell divisions. A differentiated cell may derivefrom a multipotent cell which itself is derived from a multipotent cell,and so on. While each of these multipotent cells may be considered stemcells, the range of cell types each can give rise to may varyconsiderably. Some differentiated cells also have the capacity to giverise to cells of greater developmental potential. Such capacity may benatural or may be induced artificially upon treatment with variousfactors. By this definition, stem cells may also be progenitor cells, aswell as the more immediate precursors to terminally differentiatedcells. Exemplary precursor cells involved in bone and cartilageformation include osteoprogenitor cells such as for example mesenchymalprecursors cells, osteoblasts, and chondroblasts. As used herein, anucleic acid or other molecule attached to an array, is referred to as a“probe” or “capture probe.” When an array contains several probescorresponding to one gene, these probes are referred to as “gene-probeset.” A gene-probe set can consist of, e.g., 2 to 10 probes, preferablyfrom 2 to 5 probes and most preferably about 5 probes.

[0068] A “significant similarity” between the level of expression of agene in two cells or tissues generally refers to a difference inexpression levels of a factor of at most about 10% (i.e., 1.1 fold), 25%(i.e., 1.25 fold), 50% (i.e., 1.5 fold), 75% (i.e., 1.75 fold), 90%(i.e., 1.9 fold), 2 fold, 2.5 fold, 3 fold, 5 fold, or 10 fold.Expression levels can be raw data or they can averaged or normalizeddata, e.g., normalized relative to normal controls. A “significantdifference” between the level of expression of a gene in two cells ortissues generally refers to a difference in expression levels of afactor of at least about 10% (i.e., 1.1 fold), 25% (i.e., 1.25 fold),50% (i.e., 1.5 fold), 75% (i.e., 1.75 fold), 90% (i.e., 1.9 fold), 2fold, 2.5 fold, 3 fold, 5 fold, 10 fold, 50 fold or 100 fold. Whetherthe expression of a particular gene in two samples is significantlydifferent or similar also depends on the gene itself and, e.g., itsvariability in expression between different individuals. It is withinthe skill in the art to determine whether expression levels aresignificantly similar or different.

[0069] An expression profile in one cell or tissue is “significantlysimilar” to an expression profile in another cell or tissue when thelevel of expression of the genes in the two expression profiles aresufficiently similar that the similarity is indicative of a commoncharacteristic, e.g., being of the same cell type, or beingcharacteristic of a disease. “Similarity” between an expression profileof a cell or tissue, e.g., of a subject, and a set of data representingan expression profile characteristic of a disease can be based on thepresence or absence in the cell or tissue of certain RNAs and/or certainlevels of certain RNAs of genes having a high probability of beingassociated with the disease. A high probability of being associated witha disease can be, e.g., the presence of RNA or of certain levels of RNAof particular genes which are over-expressed or under-expressed, in atleast about 50%, 60%, 70%, 80%, 90%, or 100% of patients having thedisease. A similarity with an expression profile of a patient can bebased on higher or lower expression levels of a factor of at most about10%, 25%, 50%, 75%, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 5 fold or 10fold of at least about 50%, 60%, 70%, 80%, 90%, or 100% of genes, or atleast about 10, 50, 100, 200, 300 genes, that are up- or down-regulatedin at least about 50%, 60%, 70%, 80%, 90%, or 100% of patients.

[0070] “Small molecule” as used herein, is meant to refer to acomposition, which has a molecular weight of less than about 5 kD andmost preferably less than about 4 kD. Small molecules can be nucleicacids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids orother organic (carbon-containing) or inorganic molecules. Manypharmaceutical companies have extensive libraries of chemical and/orbiological mixtures, often fungal, bacterial, or algal extracts, whichcan be screened with any of the assays of the invention to identifycompounds that modulate a bioactivity.

[0071] The term “specific hybridization” of a probe to a target site ofa template nucleic acid refers to hybridization of the probepredominantly to the target, such that the hybridization signal can beclearly interpreted. As further described herein, such conditionsresulting in specific hybridization vary depending on the length of theregion of homology, the GC content of the region, the meltingtemperature “Tm” of the hybrid. Hybridization conditions will thus varyin the salt content, acidity, and temperature of the hybridizationsolution and the washes.

[0072] A “subject” can be a mammal, e.g., a human, primate, ovine,bovine, porcine, equine, feline, canine and a rodent (rat or mouse).

[0073] The term “treating” a disease in a subject or “treating” asubject having a disease refers to providing the subject with apharmaceutical treatment, e.g., the administration of a drug, such thatat least one symptom of the disease is decreased. Treating a disease canbe preventing the disease, improving the disease or curing the disease.

[0074] The phrase “value representing the level of expression of a gene”refers to a raw number which reflects the mRNA or polypeptide level of aparticular gene in a cell or biological sample, e.g., obtained fromanalytical tools for measuring RNA or polypeptide levels.

[0075] A “variant” of a polypeptide refers to a polypeptide having theamino acid sequence of the polypeptide, in which one or more amino acidresidues are altered. The variant may have “conservative” changes,wherein a substituted amino acid has similar structural or chemicalproperties (e.g., replacement of leucine with isoleucine). More rarely,a variant may have “nonconservative” changes (e.g., replacement ofglycine with tryptophan). Analogous minor variations may also includeamino acid deletions or insertions, or both. Guidance in determiningwhich amino acid residues may be substituted, inserted, or deletedwithout abolishing biological or immunological activity may be foundusing computer programs well known in the art, for example, LASERGENEsoftware (DNASTAR). The term “variant,” when used in the context of apolynucleotide sequence, encompasses a polynucleotide sequence relatedto that of a gene of interest or the coding sequence thereof. Thisdefinition may also include, for example, “allelic,” “splice,”“species,” or “polymorphic” variants. A splice variant may havesignificant identity to a reference molecule, but will generally have agreater or lesser number of polynucleotides due to alternate splicing ofexons during mRNA processing. The corresponding polypeptide may possessadditional functional domains or an absence of domains. Species variantsare polynucleotide sequences that vary from one species to another. Theresulting polypeptides generally will have significant amino acididentity relative to each other. A polymorphic variant is a variation inthe polynucleotide sequence of a particular gene between individuals ofa given species. Polymorphic variants also may encompass “singlenucleotide polymorphisms” (SNPs) in which the polynucleotide sequencevaries by one base. The presence of SNPs may be indicative of, forexample, a certain population, a disease state, or a propensity for adisease state.

[0076] 2. Diagnostic and Prognostic Methods and Compositions

[0077] The invention provides gene expression profiles over time duringbone formation, e.g., endochondral bone formation induced by BMP-2.Since these expression profiles are characteristic of bone and cartilageformation, measuring the level of expression or level of product of oneor more genes identified in these expression profiles, e.g., genes setforth in Tables 1, 2, 5, 6 and/or 7, during bone or cartilage formationis expected to reveal any abnormalities in these processes.Abnormalities can then be treated appropriately, such as describedbelow.

[0078] Exemplary situations in which one may wish to monitor bone orcartilage formation or resorption include diseases relating to bone orcartilage formation or bone or cartilage resorption, such asosteodystrophy, osteohypertrophy, osteoblastoma, osteopertrusis,osteogenesis imperfecta, osteoporosis, osteopenia, osteoma andosteoblastoma; periondontal disease; hyperparathyroidism; hypercalcemiaof malignancy; Paget's disease; osteolytic lesions produced by bonemetastasis; bone loss due to immobilization or sex hormone deficiency;bone and cartilage loss cause by an inflammatory disease, e.g.,rheumatoid arthritis and osteoarthritis; wound healing and relatedtissue repair (e.g., burns, incisions and ulcers) and bone fractures.Bone or cartilage formation or resoption can also be monitored duringtreatment of any of the above-mentioned diseases and any conditions inwhich bone or cartilage formation is induced, such as by therapeutics,e.g., bone morphogenetic proteins. Situations in which bone or cartilageformation may be induced include healing of fractures, e.g., in closedand open fracture reduction; improved fixation of artificial joints;repair of congenital, trauma induced, or oncologic resection inducedcraniofacial defects; tooth repair processes and plastic, e.g., cosmeticplastic, surgery.

[0079] Accordingly, the invention provides methods for diagnosing andmonitoring the development of any disease relating to bone or cartilageformation or resorption, such as the diseases set forth above. Themethods of the invention also allow to distinguish one disease fromanother, where such distinction is not possible based on phenotypic orhistologic examination.

[0080] In yet another embodiment, the methods of the invention allow thedetermination of the stage of a particular disease. For example, byknowing the level of expression of certain genes, the state of bone orcartilage development can be established.

[0081] The methods of the invention can also be used to monitor thetreatment of a disease. Monitoring will reveal whether a subject isresponsive to a treatment or whether the treatment should be modified.

[0082] Measuring the level of expression or the level of product of oneor more genes described herein can also be used in prognostics, such asto determine whether a subject is likely to develop a disease relatingto bone or cartilage formation or resorption. For example a subjectwhose family is associated with such disorders can be monitored todetermine whether he or she will develop such a disorder.

[0083] Another situation during which gene expression can be monitoredis during in vitro bone or cartilage formation, e.g., induced by a bonemorphogenetic protein. In vitro synthesized bone or cartilage can beused for implanting into subject in need thereof, such as subjectshaving suffered bone loss, e.g., resulting from cancer or osteoporosis.

[0084] In one embodiment, a sample is obtained from a subject, e.g., ahuman subject, and the level of expression of one or more genes, such asgenes listed in any of Tables 1, 2, 5, 6 and/or 7, is determined. Theparticular method used for obtaining a sample will depend on the site ofthe sample to be obtained. Samples can be obtained according to methodsknown in the art. As few as one cell may be sufficient for determininggene expression. In other embodiments, the presence of proteins isdetermined in a bodily fluid, e.g., blood or synovial fluid. Geneexpression can be determined according to methods known in the art, suchas reverse transcriptase polymerase chain reaction (RT-PCR); nucleicacid arrays; dotblots; and in situ hybridization, as further describedherein. In other embodiments, the level of protein is measured, such asby immunohistochemistry, ELISA, or immunoprecipitation.

[0085] In certain embodiments, several samples are obtainedconsecutively, and a change of expression is monitored over time. Forexample, samples may be obtained about every 1, 2, 3, 5, 6, 12, 24, 36or 48 hours.

[0086] The level of expression of one or more genes in a sample can becompared to the level of expression of these genes in a control sample.A control sample may be obtained, e.g., from the same patient, but at adifferent site, or from a healthy subject. Alternatively, the level ofexpression of the genes in the sample is compared to values stored in adata-readable medium, such as the values set forth in Tables 1, 2, 5, 6and/or 7 or in FIG. 1 or 2 or 3. The comparison can be conductedvisually, or via a computer.

[0087] The presence of a bone or cartilage related disease or a defectin the treatment of such a disease may be indicated by differences inthe level of expression of one or more genes in a sample and in thecontrol sample. The differences in gene expression may be a differenceof a factor of at least about 50%; 2; 3; 5; 10; 20; 50; or 100 fold. Inother embodiments, an abnormality is revealed by comparing the level ofexpression of one or more genes over time with their expression in acontrol or healthy subject.

[0088] The diagnostic and prognostic assays may indicate a defect incartilage or bone formation or the existence of inefficient treatment ofa disease or healing, e.g., bone fracture healing. The assays may thusbe followed by a proper treatment or correction of treatment. Exemplarytreatments are provided below. Generally, any therapeutic known tocorrect the diagnosed abnormality can be used. For example, defectivebone or cartilage formation may be corrected by administration of a bonemorphogenetic protein (BMP), e.g., BPM-2 or BMP-4.

[0089]2.1. Use of Arrays for Determining the Level of Expression ofGenes

[0090] Generally, determining expression profiles with arrays involvesthe following steps: (a) obtaining a mRNA sample from a subject andpreparing labeled nucleic acids therefrom (the “target nucleic acids” or“targets”); (b) contacting the target nucleic acids with the array underconditions sufficient for target nucleic acids to bind withcorresponding probes on the array, e.g. by hybridization or specificbinding; (c) optionally removing unbound targets from the array; (d)detecting bound targets, and (e) analyzing the results. As used herein,“nucleic acid probes”, or “probes” are nucleic acids attached to thearray, whereas “target nucleic acids” are nucleic acids that arehybridized to the array. Each of these steps is described in more detailbelow.

[0091] (i) Obtaining a mRNA Sample of a Subject

[0092] In one embodiment, one or more cells from the subject to betested are obtained and RNA is isolated from the cells. In a preferredembodiment, a sample of bone, cartilage, mesenchymal cells, synovialfluid, synovium, tumor or other tissue likely to be affected by thedisorder to be diagnosed or monitored, are obtained from the subjectaccording to methods known in the art. Cells from which expressionlevels may be obtained include macrophages, fibroblasts,chondrocyte-like cells, chondrocytes, chondroblasts, bone marrow cells,osteoblast, osteocytes, osteoclasts, and osteogenic precursor cells,e.g., mesenchymal cells. When obtaining the cells, it is preferable toobtain a sample containing predominantly cells of the desired type,e.g., a sample of cells in which at least about 50%, preferably at leastabout 60%, even more preferably at least about 70%, 80% and even morepreferably, at least about 90% of the cells are of the desired type. Ahigher percentage of cells of the desired type is preferable, since sucha sample is more likely to provide clear gene expression data.

[0093] It is also possible to obtain a cell sample from a subject, andthen to enrich it for a desired cell type. Cells can also be isolatedfrom other cells using a variety of techniques, such as isolation withan antibody binding to an epitope on the cell surface of the desiredcell type. Another method that can be used includes negative selectionusing antibodies to cell surface markers to selectively enrich for aspecific cell type without activating the cell by receptor engagement.Where the desired cells are in a solid tissue, particular cells can bedissected out, e.g., by microdissection. Exemplary cells that one maywant to enrich for include mesenchymal cells, such as muscularmesenchymal cells, osteoblasts, osteocytes, chondroblasts, chondrocytes,tumor cells and other bone or cartilage cells.

[0094] In one embodiment, RNA is obtained from a single cell. Forexample, a cell can be isolated from a tissue sample by laser capturemicrodissection (LCM). Using this technique, a cell can be isolated froma tissue section, including a stained tissue section, thereby assuringthat the desired cell is isolated (see, e.g., Bonner et al. (1997)Science 278: 1481; Emmert-Buck et al. (1996) Science 274:998; Fend etal. (1999) Am. J. Path. 154: 61 and Murakami et al. (2000) Kidney Int.58:1346). For example, Murakami et al., supra, describe isolation of acell from a previously immunostained tissue section.

[0095] It is also be possible to obtain cells from a subject and culturethe cells in vitro, such as to obtain a larger population of cells fromwhich RNA can be extracted. Methods for establishing cultures ofnon-transformed cells, i.e., primary cell cultures, are known in theart.

[0096] When isolating RNA from tissue samples or cells from individuals,it may be important to prevent any further changes in gene expressionafter the tissue or cells has been removed from the subject. Changes inexpression levels are known to change rapidly following perturbations,e.g., heat shock or activation with lipopolysaccharide (LPS) or otherreagents. In addition, the RNA in the tissue and cells may quicklybecome degraded. Accordingly, in a preferred embodiment, the tissue orcells obtained from a subject is snap frozen as soon as possible.

[0097] RNA can be extracted from the tissue sample by a variety ofmethods, e.g., those described in the Examples or guanidium thiocyanatelysis followed by CsCl centrifugation (Chirgwin et al., 1979,Biochemistry 18:5294-5299). RNA from single cells can be obtained asdescribed in methods for preparing cDNA libraries from single cells,such as those described in Dulac, C. (1998) Curr. Top. Dev. Biol. 36,245 and Jena et al. (1996) J. Immunol. Methods 190:199. Care to avoidRNA degradation must be taken, e.g., by inclusion of RNAsin.

[0098] The RNA sample can then be enriched in particular species. In oneembodiment, poly(A)+ RNA is isolated from the RNA sample. In general,such purification takes advantage of the poly-A tails on mRNA. Inparticular and as noted above, poly-T oligonucleotides may beimmobilized on a solid support to serve as affinity ligands for mRNA.Kits for this purpose are commercially available, e.g., the MessageMakerkit (Life Technologies, Grand Island, N.Y.).

[0099] In a preferred embodiment, the RNA population is enriched insequences of interest, such as those of genes listed in Tables 1, 2, 5,6 and/or 7. Enrichment can be undertaken, e.g., by primer-specific cDNAsynthesis, or multiple rounds of linear amplification based on cDNAsynthesis and template-directed in vitro transcription (see, e.g., Wanget al. (1989) PNAS 86, 9717; Dulac et al., supra, and Jena et al.,supra).

[0100] The population of RNA, enriched or not in particular species orsequences, can further be amplified. Such amplification is particularlyimportant when using RNA from a single or a few cells. A variety ofamplification methods are suitable for use in the methods of theinvention, including, e.g., PCR; ligase chain reaction (LCR) (See, e.g.,Wu and Wallace, Genomics 4, 560 (1989), Landegren et al., Science 241,1077 (1988)); self-sustained sequence replication (SSR) (see, e.g.,Guatelli et al., Proc. Nat. Acad. Sci. USA, 87, 1874 (1990)); nucleicacid based sequence amplification (NASBA) and transcriptionamplification (see, e.g., Kwoh et al., Proc. Natl. Acad. Sci. USA 86,1173 (1989)). For PCR technology, see, e.g., PCR Technology: Principlesand Applications for DNA Amplification (ed. H. A. Erlich, Freeman Press,N.Y., N.Y., 1992); PCR Protocols: A Guide to Methods and applications(eds. Innis, et al., Academic Press, San Diego, Calif., 1990); Mattilaet al., Nucleic Acids Res. 19, 4967 (1991); Eckert et al., PCR Methodsand Applications 1, 17 (1991); PCR (eds. McPherson et al., IRL Press,Oxford); and U.S. Pat. No. 4,683,202. Methods of amplification aredescribed, e.g., in Ohyama et al. (2000) BioTechniques 29:530; Luo etal. (1999) Nat. Med. 5, 117; Hegde et al. (2000) BioTechniques 29:548;Kacharmina et al. (1999) Meth. Enzymol. 303:3; Livesey et al. (2000)Curr. Biol. 10:301; Spirin et al. (1999) Invest. Ophtalmol. Vis. Sci.40:3108; and Sakai et al. (2000) Anal. Biochem. 287:32. RNAamplification and cDNA synthesis can also be conducted in cells in situ(see, e.g., Eberwine et al. (1992) PNAS 89:3010).

[0101] One of skill in the art will appreciate that whateveramplification method is used, if a quantitative result is desired, caremust be taken to use a method that maintains or controls for therelative frequencies of the amplified nucleic acids to achievequantitative amplification. Methods of “quantitative” amplification arewell known to those of skill in the art. For example, quantitative PCRinvolves simultaneously co-amplifying a known quantity of a controlsequence using the same primers. This provides an internal standard thatmay be used to calibrate the PCR reaction. A high density array may theninclude probes specific to the internal standard for quantification ofthe amplified nucleic acid.

[0102] One preferred internal standard is a synthetic AW106 cRNA. TheAW106 ERNA is combined with RNA isolated from the sample according tostandard techniques known to those of skilled in the art. The RNA isthen reverse transcribed using a reverse transcriptase to provide copyDNA. The cDNA sequences are then amplified (e.g., by PCR) using labeledprimers. The amplification products are separated, typically byelectrophoresis, and the amount of radioactivity (proportional to theamount of amplified product) is determined. The amount of mRNA in thesample is then calculated by comparison with the signal produced by theknown AW106 RNA standard. Detailed protocols for quantitative PCR areprovided in PCR Protocols, A Guide to Methods and Applications, Innis etal., Academic Press, Inc. N.Y., (1990).

[0103] In a preferred embodiment, a sample mRNA is reverse transcribedwith a reverse transcriptase and a primer consisting of oligo(dT) and asequence encoding the phage T7 promoter to provide single stranded DNAtemplate. The second DNA strand is polymerized using a DNA polymerase.After synthesis of double-stranded cDNA, T7 RNA polymerase is added andRNA is transcribed from the cDNA template. Successive rounds oftranscription from each single cDNA template results in amplified RNA.Methods of in vitro polymerization are well known to those of skill inthe art (See, e.g., Sambrook, (supra) and this particular method isdescribed in detail by Van Gelder, et al., Proc. Natl. Acad. Sci. USA,87: 1663-1667 (1990) who demonstrate that in vitro amplificationaccording to this method preserves the relative frequencies of thevarious RNA transcripts). Moreover, Eberwine et al. Proc. Natl. Acad.Sci. USA, 89: 3010-3014 provide a protocol that uses two rounds ofamplification via in vitro transcription to achieve greater than 106fold amplification of the original starting material, thereby permittingexpression monitoring even where biological samples are limited.

[0104] It will be appreciated by one of skill in the art that the directtranscription method described above provides an antisense (aRNA) pool.Where antisense RNA is used as the target nucleic acid, theoligonucleotide probes provided in the array are chosen to becomplementary to subsequences of the antisense nucleic acids.Conversely, where the target nucleic acid pool is a pool of sensenucleic acids, the oligonucleotide probes are selected to becomplementary to subsequences of the sense nucleic acids. Finally, wherethe nucleic acid pool is double stranded, the probes may be of eithersense as the target nucleic acids include both sense and antisensestrands.

[0105] (ii) Labeling of the Nucleic Acids to be Analyzed

[0106] Generally, the target molecules will be labeled to permitdetection of hybridization of target molecules to a microarray. By“labeled” is meant that the probe comprises a member of a signalproducing system and is thus detectable, either directly or throughcombined action with one or more additional members of a signalproducing system. Examples of directly detectable labels includeisotopic and fluorescent moieties incorporated into, usually covalentlybonded to, a moiety of the probe, such as a nucleotide monomeric unit,e.g. dNMP of the primer, or a photoactive or chemically activederivative of a detectable label which can be bound to a functionalmoiety of the probe molecule.

[0107] Nucleic acids can be labeled after or during enrichment and/oramplification of RNAs. For example, labeled cDNA can be prepared frommRNA by oligo dT-primed or random-primed reverse transcription, both ofwhich are well known in the art (see, e.g., Klug and Berger, 1987,Methods Enzymol. 152:316-325). Reverse transcription may be carried outin the presence of a dNTP conjugated to a detectable label, mostpreferably a fluorescently labeled dNTP. Alternatively, isolated mRNAcan be converted to labeled antisense RNA synthesized by in vitrotranscription of double-stranded cDNA in the presence of labeled dNTPs(Lockhart et al., 1996, Expression monitoring by hybridization tohigh-density oligonucleotide arrays, Nature Biotech. 14:1675). Inalternative embodiments, the cDNA or RNA probe can be synthesized in theabsence of detectable label and may be labeled subsequently, e.g., byincorporating biotinylated dNTPs or rNTP, or some similar means (e.g.,photo-cross-linking a psoralen derivative of biotin to RNAs), followedby addition of labeled streptavidin (e.g., phycoerythrin-conjugatedstreptavidin) or the equivalent.

[0108] In one embodiment, labeled cDNA is synthesized by incubating amixture containing RNA and 0.5 mM dGTP, dATP and dCTP plus 0.1 mM dTTPplus fluorescent deoxyribonucleotides (e.g., 0.1 mM Rhodamine 110 UTP(Perken Elmer Cetus) or 0.1 mM Cy3 dUTP (Amersham)) with reversetranscriptase (e.g., SuperScript.™0.11, LTI Inc.) at 42° C. for 60 min.

[0109] Fluorescent moieties or labels of interest include coumarin andits derivatives, e.g. 7-amino-4-methylcoumarin, aminocoumarin, bodipydyes, such as Bodipy FL, cascade blue, fluorescein and its derivatives,e.g. fluorescein isothiocyanate, Oregon green, rhodamine dyes, e.g.Texas red, tetramethylrhodamine, eosins and erythrosins, cyanine dyes,e.g. Cy2, Cy3, Cy3.5, Cy5, Cy5.5, Cy7, Fluor X, macrocyclic chelates oflanthanide ions, e.g. quantum dye™, fluorescent energy transfer dyes,such as thiazole orange-ethidium heterodimer, TOTAB, dansyl, etc.Individual fluorescent compounds which have functionalities for linkingto an element desirably detected in an apparatus or assay of theinvention, or which can be modified to incorporate such functionalitiesinclude, e.g., dansyl chloride; fluoresceins such as3,6-dihydroxy-9-phenylxanthydrol; rhodamineisothiocyanate; N-phenyl1-amino-8-sulfonatonaphthalene; N-phenyl 2-amino-6-sulfonatonaphthalene;4-acetamido-4-isothiocyanatostilbene-2,2′-disulfonic acid;pyrene-3-sulfonic acid; 2-toluidinonaphthalene-6-sulfonate;Nphenyl-N-methyl-2-aminoaphthalene-6-sulfonate; ethidium bromide;stebrine; auromine-0,2-(9′-anthroyl)palmitate; dansylphosphatidylethanolamine; N,N′-dioctadecyl oxacarbocyanine: N,N′dihexyloxacarbocyanine; merocyanine, 4-(3′-pyrenyl)stearate;d-3-aminodesoxy-equilenin; 12-(9′-anthroyl)stearate; 2-methylanthracene;9-vinylanthracene; 2,2′(vinylene-p-phenylene)bisbenzoxazole;p-bis(2-methyl-5-phenyl-oxazolyl))benzene;6-dimethylamino-1,2-benzophenazin; retinol; bis(3′-aminopyridinium)1,10-decandiyl dilodide; sulfonaphthylhydrazone of hellibrienin;chlorotetracycline;N-(7-dimethylamino-4-methyl-2-oxo-3-chromenyl)maleimide;N-(p-(2-benzimidazolyl)-phenyl)maleimide; N-(4-fluoranthyl)maleimide;bis(homovanillic acid); resazarin;4-chloro-7-nitro-2,1,3-benzooxadiazole; merocyanine 540; resorufin; rosebengal; and 2,4-diphenyl-3(2H)-furanone. (see, e.g., Kricka, 1992,Nonisotopic DNA Probe Techniques, Academic Press San Diego, Calif.).Many fluorescent tags are commercially available from SIGMA chemicalcompany (Saint Louis, Mo.), Amersham, Molecular Probes, R&D systems(Minneapolis, Minn.), Pharmacia LKB Biotechnology (Piscataway, N.J.),CLONTECH Laboratories, Inc. (Palo Alto, Calif.), Chem Genes Corp.,Aldrich Chemical Company (Milwaukee, Wis.), Glen Research, Inc., GIBCOBRL Life Technologies, Inc. (Gaithersberg, Md.), FlukaChemica-Biochemika Analytika (Fluka Chemie AG, Buchs, Switzerland), andApplied Biosystems (Foster City, Calif.) as well as other commercialsources known to one of skill.

[0110] Chemiluminescent labels include luciferin and2,3-dihydrophthalazinediones, e.g., luminol.

[0111] Isotopic moieties or labels of interest include ³²P, ³³P, ³⁵S,¹²⁵I, ²H, ¹⁴C, and the like (see Zhao et al., 1995, High density cDNAfilter analysis: a novel approach for large-scale, quantitative analysisof gene expression, Gene 156:207; Pietu et al., 1996, Novel genetranscripts preferentially expressed in human muscles revealed byquantitative hybridization of a high density cDNA array, Genome Res.6:492).

[0112] Labels may also be members of a signal producing system that actin concert with one or more additional members of the same system toprovide a detectable signal. Illustrative of such labels are members ofa specific binding pair, such as ligands, e.g. biotin, fluorescein,digoxigenin, antigen, polyvalent cations, chelator groups and the like,where the members specifically bind to additional members of the signalproducing system, where the additional members provide a detectablesignal either directly or indirectly, e.g. antibody conjugated to afluorescent moiety or an enzymatic moiety capable of converting asubstrate to a chromogenic product, e.g. alkaline phosphatase conjugateantibody and the like.

[0113] Additional labels of interest include those that provide forsignal only when the probe with which they are associated isspecifically bound to a target molecule, where such labels include:“molecular beacons” as described in Tyagi & Kramer, Nature Biotechnology(1996) 14:303 and EP 0 070 685 B1. Other labels of interest includethose described in U.S. Pat. No. 5,563,037; WO 97/17471 and WO 97/17076.

[0114] In some cases, hybridized target nucleic acids may be labeledfollowing hybridization. For example, where biotin labeled dNTPs areused in, e.g., amplification or transcription, streptavidin linkedreporter groups may be used to label hybridized complexes.

[0115] In other embodiments, the target nucleic acid is not labeled. Inthis case, hybridization can be determined, e.g., by plasmon resonance,as described, e.g., in Thiel et al. (1997) Anal. Chem. 69:4948.

[0116] In one embodiment, a plurality (e.g., 2, 3, 4, 5 or more) of setsof target nucleic acids are labeled and used in one hybridizationreaction (“multiplex” analysis). For example, one set of nucleic acidsmay correspond to RNA from one cell or tissue sample and another set ofnucleic acids may correspond to RNA from another cell or tissue sample.The plurality of sets of nucleic acids can be labeled with differentlabels, e.g., different fluorescent labels which have distinct emissionspectra so that they can be distinguished. The sets can then be mixedand hybridized simultaneously to one microarray.

[0117] For example, the two different cells can be a cell of a subjectsuspected of having a disease related to bone or cartilage formation orresoprtion and a counterpart normal cell. In another embodiment, e.g.,for identifying drugs modulating bone formation, one biological samplecontains cells that were exposed to a drug and the other biologicalsample contains cells that were not exposed to the drug. The cDNAderived from each of the two cell types are differently labeled so thatthey can be distinguished. In one embodiment, for example, cDNA from onesample is synthesized using a fluorescein-labeled dNTP, and cDNA fromthe second sample is synthesized using a rhodamine-labeled dNTP. Whenthe two cDNAs are mixed and hybridized to the microarray, the relativeintensity of signal from each cDNA set is determined for each site onthe array, and any relative difference in abundance of a particular mRNAdetected.

[0118] In the example described above, the cDNA from one sample willfluoresce green when the fluorophore is stimulated and the cDNA from thesecond sample will fluoresce red. As a result, if the two cells areessentially the same, the particular mRNA will be equally prevalent inboth cells and, upon reverse transcription, red-labeled andgreen-labeled cDNA will be equally prevalent. When hybridized to themicroarray, the binding site(s) for that species of RNA will emitwavelengths characteristic of both fluorophores (and appear brown incombination). In contrast, if the two cells are different, the ratio ofgreen to red fluorescence will be different.

[0119] The use of a two-color fluorescence labeling and detection schemeto define alterations in gene expression has been described, e.g., inShena et al., 1995, Quantitative monitoring of gene expression patternswith a complementary DNA microarray, Science 270:467-470. An advantageof using cDNA labeled with two different fluorophores is that a directand internally controlled comparison of the mRNA levels corresponding toeach arrayed gene in two cell states can be made, and variations due tominor differences in experimental conditions (e.g, hybridizationconditions) will not affect subsequent analyses.

[0120] Examples of distinguishable labels for use when hybridizing aplurality of target nucleic acids to one array are well known in the artand include: two or more different emission wavelength fluorescent dyes,like Cy3 and Cy5, combination of fluorescent proteins and dyes, likephicoerythrin and CyS, two or more isotopes with different energy ofemission, like ³²P and ³³P, gold or silver particles with differentscattering spectra, labels which generate signals under differenttreatment conditions, like temperature, pH, treatment by additionalchemical agents, etc., or generate signals at different time pointsafter treatment. Using one or more enzymes for signal generation allowsfor the use of an even greater variety of distinguishable labels, basedon different substrate specificity of enzymes (alkalinephosphatase/peroxidase).

[0121] Further, it is preferable in order to reduce experimental errorto reverse the fluorescent labels in two-color differentialhybridization experiments to reduce biases peculiar to individual genesor array spot locations. In other words, it is preferable to firstmeasure gene expression with one labeling (e.g., labeling nucleic acidfroma first cell with a first fluorochrome and nucleic acid from asecond cell with a second fluorochrome) of the mRNA from the two cellsbeing measured, and then to measure gene expression from the two cellswith reversed labeling (e.g., labeling nucleic acid from the first cellwith the second fluorochrome and nucleic acid from the second cell withthe first fluorochrome). Multiple measurements over exposure levels andperturbation control parameter levels provide additional experimentalerror control.

[0122] The quality of labeled nucleic acids can be evaluated prior tohybridization to an array. For example, a sample of the labeled nucleicacids can be hybridized to probes derived from the 5′, middle and 3′portions of genes known to be or suspected to be present in the nucleicacid sample. This will be indicative as to whether the labeled nucleicacids are full length nucleic acids or whether they are degraded. In oneembodiment, the GeneChip® Test3 Array from Affymetrix (Santa Clara,Calif.) can be used for that purpose. This array contains probesrepresenting a subset of characterized genes from several organismsincluding mammals. Thus, the quality of a labeled nucleic acid samplecan be determined by hybridization of a fraction of the sample to anarray, such as the GeneChip® Test3 Array from Affymetrix (Santa Clara,Calif.).

[0123] (iii) Exemplary Arrays

[0124] Preferred arrays, e.g., microarrays, for use according to theinvention include one or more probes of genes which are up- ordown-regulated during bone or cartilage formation, such as one or moregenes listed in any of Tables 1, 2, 5, 6 and/or 7. The array maycomprise probes corresponding to at least 10, preferably at least 20, atleast 50, at least 100 or at least 1000 genes. The array may compriseprobes corresponding to about 10%, 20%, 50%, 70%, 90% or 95% of thegenes listed in any of Tables 1, 2, 5, 6 and/or 7. The array maycomprise probes corresponding to about 10%, 20%, 50%, 70%, 90% or 95% ofthe genes listed in any of Tables 1, 2, 5, 6 and/or 7 whose expressionincreases or decreases at least about 2 fold, preferably at least about3 fold, more preferably at least about 4 fold, 5 fold, 7 fold and mostpreferably at least about 10 fold during bone or cartilage formation.One array that can be used is the array used and described in theExamples.

[0125] There can be one or more than one probe corresponding to eachgene on a microarray. For example, a microarray may contain from 2 to 20probes corresponding to one gene and preferably about 5 to 10. Theprobes may correspond to the full length RNA sequence or complementthereof of genes that are up- or down-regulated during bone or cartilageformation, or they may correspond to a portion thereof, which portion isof sufficient length for permitting specific hybridization. Such probesmay comprise from about 50 nucleotides to about 100, 200, 500, or 1000nucleotides or more than 1000 nucleotides. As further described herein,microarrays may contain oligonucleotide probes, consisting of about 10to 50 nucleotides, preferably about 15 to 30 nucleotides and even morepreferably 20-25 nucleotides. The probes are preferably single stranded.The probe will have sufficient complementarity to its target to providefor the desired level of sequence specific hybridization (see below).

[0126] Typically, the arrays used in the present invention will have asite density of greater than 100 different probes per cm². Preferably,the arrays will have a site density of greater than 500/cm², morepreferably greater than about 1000/cm², and most preferably, greaterthan about 10,000/cm². Preferably, the arrays will have more than 100different probes on a single substrate, more preferably greater thanabout 1000 different probes still more preferably, greater than about10,000 different probes and most preferably, greater than 100,000different probes on a single substrate.

[0127] Microarrays can be prepared by methods known in the art, asdescribed below, or they can be custom made by companies, e.g.,Affymetrix (Santa Clara, Calif.).

[0128] Generally, two types of microarrays can be used. These two typesare referred to as “synthesis” and “delivery.” In the synthesis type, amicroarray is prepared in a step-wise fashion by the in situ synthesisof nucleic acids from nucleotides. With each round of synthesis,nucleotides are added to growing chains until the desired length isachieved. In the delivery type of microarray, preprepared nucleic acidsare deposited onto known locations using a variety of deliverytechnologies. Numerous articles describe the different microarraytechnologies, e.g., Shena et al. (1998) Tibtech 16: 301; Duggan et al.(1999) Nat. Genet. 21:10; Bowtell et al. (1999) Nat. Genet. 21: 25.

[0129] One novel synthesis technology is that developed by Affymetrix(Santa Clara, Calif.), which combines photolithography technology withDNA synthetic chemistry to enable high density oligonucleotidemicroarray manufacture. Such chips contain up to 400,000 groups ofoligonucleotides in an area of about 1.6 cm². Oligonucleotides areanchored at the 3′ end thereby maximizing the availability ofsingle-stranded nucleic acid for hybridization. Generally such chips,referred to as “GeneChipso” contain several oligonucleotides of aparticular gene, e.g., between 15-20, such as 16 oligonucleotides. SinceAffymetrix (Santa Clara, Calif.) sells custom made microarrays,microarrays containing genes which are up- or down-regulated during boneformation can be ordered for purchase from Affymetrix (Santa Clara,Calif.).

[0130] Microarrays can also be prepared by mechanical microspotting,e.g., those commercialized at Synteni (Fremont, Calif.). According tothese methods, small quantities of nucleic acids are printed onto solidsurfaces. Microspotted arrays prepared at Synteni contain as many as10,000 groups of cDNA in an area of about 3.6 cm².

[0131] A third group of microarray technologies consist in the“drop-on-demand” delivery approaches, the most advanced of which are theink-jetting technologies, which utilize piezoelectric and other forms ofpropulsion to transfer nucleic acids from miniature nozzles to solidsurfaces. Inkjet technologies is developed at several centers includingIncyte Pharmaceuticals (Palo Alto, Calif.) and Protogene (Palo Alto,Calif.). This technology results in a density of 10,000 spots per cm².See also, Hughes et al. (2001) Nat. Biotechn. 19:342.

[0132] Arrays preferably include control and reference nucleic acids.Control nucleic acids are nucleic acids which serve to indicate that thehybridization was effective. For example, all Affymetrix (Santa Clara,Calif.) expression arrays contain sets of probes for several prokaryoticgenes, e.g., bioB, bioC and bioD from biotin synthesis of E. coli andcre from PI bacteriophage. Hybridization to these arrays is conducted inthe presence of a mixture of these genes or portions thereof, such asthe mix provided by Affymetrix (Santa Clara, Calif.) to that effect(Part Number 900299), to thereby confirm that the hybridization waseffective. Control nucleic acids included with the target nucleic acidscan also be mRNA synthesized from cDNA clones by in vitro transcription.Other control genes that may be included in arrays are polyA controls,such as dap, lys, phe, thr, and trp (which are included on AffymetrixGeneChips®)

[0133] Reference nucleic acids allow the normalization of results fromone experiment to another, and to compare multiple experiments on aquantitative level. Exemplary reference nucleic acids includehousekeeping genes of known expression levels, e.g., GAPDH, hexokinaseand actin.

[0134] Mismatch controls may also be provided for the probes to thetarget genes, for expression level controls or for normalizationcontrols. Mismatch controls are oligonucleotide probes or other nucleicacid probes identical to their corresponding test or control probesexcept for the presence of one or more mismatched bases.

[0135] Arrays may also contain probes that hybridize to more than oneallele of a gene. For example the array can contain one probe thatrecognizes allele 1 and another probe that recognizes allele 2 of aparticular gene.

[0136] Microarrays can be prepared as follows. In one embodiment, anarray of oligonucleotides is synthesized on a solid support. Exemplarysolid supports include glass, plastics, polymers, metals, metalloids,ceramics, organics, etc. Using chip masking technologies andphotoprotective chemistry it is possible to generate ordered arrays ofnucleic acid probes. These arrays, which are known, e.g., as “DNAchips,” or as very large scale immobilized polymer arrays (“VLSIPS™”arrays) can include millions of defined probe regions on a substratehaving an area of about 1 cm² to several cm², thereby incorporating setsof from a few to millions of probes (see, e.g., U.S. Pat. No.5,631,734).

[0137] The construction of solid phase nucleic acid arrays to detecttarget nucleic acids is well described in the literature. See, Fodor etal. (1991) Science, 251: 767-777; Sheldon et al. (1993) ClinicalChemistry 39(4): 718-719; Kozal et al. (1996) Nature Medicine 2(7):753-759 and Hubbell U.S. Pat. No. 5,571,639; Pinkel et al.PCT/US95/16155 (WO 96/17958); U.S. Pat. Nos. 5,677,195; 5,624,711;5,599,695; 5,451,683; 5,424,186; 5,412,087; 5,384,261; 5,252,743 and5,143,854; PCT Patent Publication Nos. 92/10092 and 93/09668; and PCT WO97/10365. In brief, a combinatorial strategy allows for the synthesis ofarrays containing a large number of probes using a minimal number ofsynthetic steps. For instance, it is possible to synthesize and attachall possible DNA 8 mer oligonucleotides (48, or 65,536 possiblecombinations) using only 32 chemical synthetic steps. In general,VLSIPS™ procedures provide a method of producing 4n differentoligonucleotide probes on an array using only 4n synthetic steps (see,e.g., U.S. Pat. No. 5,631,734 5,143,854 and PCT Patent Publication Nos.WO 90/15070; WO 95/11995 and WO 92/10092).

[0138] Light-directed combinatorial synthesis of oligonucleotide arrayson a glass surface can be performed with automated phosphoramiditechemistry and chip masking techniques similar to photoresisttechnologies in the computer chip industry. Typically, a glass surfaceis derivatized with a silane reagent containing a functional group,e.g., a hydroxyl or amine group blocked by a photolabile protectinggroup. Photolysis through a photolithogaphic mask is used selectively toexpose functional groups which are then ready to react with incoming5′-photoprotected nucleoside phosphoramidites. The phosphoramiditesreact only with those sites which are illuminated (and thus exposed byremoval of the photolabile blocking group). Thus, the phosphoramiditesonly add to those areas selectively exposed from the preceding step.These steps are repeated until the desired array of sequences have beensynthesized on the solid surface.

[0139] Algorithms for design of masks to reduce the number of synthesiscycles are described by Hubbel et al., U.S. Pat. No. 5,571,639 and U.S.Pat. No. 5,593,839. A computer system may be used to select nucleic acidprobes on the substrate and design the layout of the array as describedin U.S. Pat. No. 5,571,639.

[0140] Another method for synthesizing high density arrays is describedin U.S. Pat. No. 6,083,697. This method utilizes a novel chemicalamplification process using a catalyst system which is initiated byradiation to assist in the synthesis the polymer sequences. Such methodsinclude the use of photosensitive compounds which act as catalysts tochemically alter the synthesis intermediates in a manner to promoteformation of polymer sequences. Such photosensitive compounds includewhat are generally referred to as radiation-activated catalysts (RACs),and more specifically photo activated catalysts (PACs). The RACs can bythemselves chemically alter the synthesis intermediate or they canactivate an autocatalytic compound which chemically alters the synthesisintermediate in a manner to allow the synthesis intermediate tochemically combine with a later added synthesis intermediate or othercompound.

[0141] Arrays can also be synthesized in a combinatorial fashion bydelivering monomers to cells of a support by mechanically constrainedflowpaths. See Winkler et al., EP 624,059. Arrays can also besynthesized by spotting monomers reagents on to a support using an inkjet printer. See id. and Pease et al., EP 728,520.

[0142] cDNA probes can be prepared according to methods known in the artand further described herein, e.g., reverse-transcription PCR (RT-PCR)of RNA using sequence specific primers. Oligonucleotide probes can besynthesized chemically. Sequences of the genes or cDNA from which probesare made can be obtained, e.g., from GenBank, other public databases orpublications.

[0143] Nucleic acid probes can be natural nucleic acids, chemicallymodified nucleic acids, e.g., composed of nucleotide analogs, as long asthey have activated hydroxyl groups compatible with the linkingchemistry. The protective groups can, themselves, be photolabile.Alternatively, the protective groups can be labile under certainchemical conditions, e.g., acid. In this example, the surface of thesolid support can contain a composition that generates acids uponexposure to light. Thus, exposure of a region of the substrate to lightgenerates acids in that region that remove the protective groups in theexposed region. Also, the synthesis method can use 3′-protected5′-O-phosphoramidite-activated deoxynucleoside. In this case, theoligonucleotide is synthesized in the 5′ to 3′ direction, which resultsin a free 5′ end.

[0144] Oligonucleotides of an array can be synthesized using a 96 wellautomated multiplex oligonucleotide synthesizer (A.M.O.S.) that iscapable of making thousands of oligonucleotides (Lashkari et al. (1995)PNAS 93: 7912) can be used.

[0145] It will be appreciated that oligonucleotide design is influencedby the intended application. For example, it may be desirable to havesimilar melting temperatures for all of the probes. Accordingly, thelength of the probes are adjusted so that the melting temperatures forall of the probes on the array are closely similar (it will beappreciated that different lengths for different probes may be needed toachieve a particular T[m] where different probes have different GCcontents). Although melting temperature is a primary consideration inprobe design, other factors are optionally used to further adjust probeconstruction, such as selecting against primer self-complementarity andthe like.

[0146] Arrays, e.g., microarrrays, may conveniently be stored followingfabrication or purchase for use at a later time. Under appropriateconditions, the subject arrays are capable of being stored for at leastabout 6 months and may be stored for up to one year or longer. Arraysare generally stored at temperatures between about −20° C. to roomtemperature, where the arrays are preferably sealed in a plasticcontainer, e.g. bag, and shielded from light.

[0147] (iv) Hybridization of the Target Nucleic Acids to the Microarray

[0148] The next step is to contact the target nucleic acids with thearray under conditions sufficient for binding between the target nucleicacids and the probes of the array. In a preferred embodiment, the targetnucleic acids will be contacted with the array under conditionssufficient for hybridization to occur between the target nucleic acidsand probes on the microarray, where the hybridization conditions will beselected in order to provide for the desired level of hybridizationspecificity.

[0149] Contact of the array and target nucleic acids involves contactingthe array with an aqueous medium comprising the target nucleic acids.Contact may be achieved in a variety of different ways depending onspecific configuration of the array. For example, where the array simplycomprises the pattern of size separated probes on the surface of a“plate-like” rigid substrate, contact may be accomplished by simplyplacing the array in a container comprising the target nucleic acidsolution, such as a polyethylene bag, and the like. In other embodimentswhere the array is entrapped in a separation media bounded by two rigidplates, the opportunity exists to deliver the target nucleic acids viaelectrophoretic means. Alternatively, where the array is incorporatedinto a biochip device having fluid entry and exit ports, the targetnucleic acid solution can be introduced into the chamber in which thepattern of target molecules is presented through the entry port, wherefluid introduction could be performed manually or with an automateddevice. In multiwell embodiments, the target nucleic acid solution willbe introduced in the reaction chamber comprising the array, eithermanually, e.g. with a pipette, or with an automated fluid handlingdevice.

[0150] Contact of the target nucleic acid solution and the probes willbe maintained for a sufficient period of time for binding between thetarget and the probe to occur. Although dependent on the nature of theprobe and target, contact will generally be maintained for a period oftime ranging from about 10 min to 24 hrs, usually from about 30 min to12 hrs and more usually from about 1 hr to 6 hrs.

[0151] When using commercially available microarrays, adequatehybridization conditions are provided by the manufacturer. When usingnon-commercial microarrays, adequate hybridization conditions can bedetermined based on the following hybridization guidelines, as well ason the hybridization conditions described in the numerous publishedarticles on the use of microarrays.

[0152] Nucleic acid hybridization and wash conditions are optimallychosen so that the probe “specifically binds” or “specificallyhybridizes” to a specific array site, i.e., the probe hybridizes,duplexes or binds to a sequence array site with a complementary nucleicacid sequence but does not hybridize to a site with a non-complementarynucleic acid sequence. As used herein, one polynucleotide sequence isconsidered complementary to another when, if the shorter of thepolynucleotides is less than or equal to 25 bases, there are nomismatches using standard base-pairing rules or, if the shorter of thepolynucleotides is longer than 25 bases, there is no more than a 5%mismatch. Preferably, the polynucleotides are perfectly complementary(no mismatches). It can easily be demonstrated that specifichybridization conditions result in specific hybridization by carryingout a hybridization assay including negative controls.

[0153] Hybridization is carried out in conditions permitting essentiallyspecific hybridization. The length of the probe and GC content willdetermine the Tm of the hybrid, and thus the hybridization conditionsnecessary for obtaining specific hybridization of the probe to thetemplate nucleic acid. These factors are well known to a person of skillin the art, and can also be tested in assays. An extensive guide to thehybridization of nucleic acids is found in Tijssen (1993), “LaboratoryTechniques in biochemistry and molecular biology-hybridization withnucleic acid probes.” Generally, stringent conditions are selected to beabout 5° C. lower than the thermal melting point (Tm) for the specificsequence at a defined ionic strength and pH. The Tm is the temperature(under defined ionic strength and pH) at which 50% of the targetsequence hybridizes to a perfectly matched probe. Highly stringentconditions are selected to be equal to the Tm point for a particularprobe. Sometimes the term “Td” is used to define the temperature atwhich at least half of the probe dissociates from a perfectly matchedtarget nucleic acid. In any case, a variety of estimation techniques forestimating the Tm or Td are available, and generally described inTijssen, supra. Typically, G-C base pairs in a duplex are estimated tocontribute about 3° C. to the Tm, while A-T base pairs are estimated tocontribute about 2° C., up to a theoretical maximum of about 80-100° C.However, more sophisticated models of Tm and Td are available andappropriate in which G-C stacking interactions, solvent effects, thedesired assay temperature and the like are taken into account. Forexample, probes can be designed to have a dissociation temperature (Td)of approximately 60° C., using the formula:Td=(((((3×#GC)+(2×#AT))×37)−562)/#bp)−5; where #GC, #AT, and #bp are thenumber of guanine-cytosine base pairs, the number of adenine-thyminebase pairs, and the number of total base pairs, respectively, involvedin the annealing of the probe to the template DNA.

[0154] The stability difference between a perfectly matched duplex and amismatched duplex, particularly if the mismatch is only a single base,can be quite small, corresponding to a difference in Tm between the twoof as little as 0.5 degrees. See Tibanyenda, N. et al., Eur. J. Biochem.139:19 (1984) and Ebel, S. et al., Biochem. 31:12083 (1992). Moreimportantly, it is understood that as the length of the homology regionincreases, the effect of a single base mismatch on overall duplexstability decreases.

[0155] Theory and practice of nucleic acid hybridization is described,e.g., in S. Agrawal (ed.) Methods in Molecular Biology, volume 20; andTijssen (1993) Laboratory Techniques in biochemistry and molecularbiology-hybridization with nucleic acid probes, e.g., part I chapter 2“Overview of principles of hybridization and the strategy of nucleicacid probe assays”, Elsevier, New York provide a basic guide to nucleicacid hybridization.

[0156] Certain microarrays are of “active” nature, i.e., they provideindependent electronic control over all aspects of the hybridizationreaction (or any other affinity reaction) occurring at each specificmicrolocation. These devices provide a new mechanism for affectinghybridization reactions which is called electronic stringency control(ESC). Such active devices can electronically produce “differentstringency conditions” at each microlocation. Thus, all hybridizationscan be carried out optimally in the same bulk solution. These arrays aredescribed in U.S. Pat. No. 6,051,380 by Sosnowski et al.

[0157] In a preferred embodiment, background signal is reduced by theuse of a detergent (e.g, C-TAB) or a blocking reagent (e.g., sperm DNA,cot-1 DNA, etc.) during the hybridization to reduce non-specificbinding. In a particularly preferred (embodiment, the hybridization isperformed in the presence of about 0.5 mg/ml DNA (e.g., herring spermDNA). The use of blocking agents in hybridization is well known to thoseof skill in the art (see, e.g., Chapter 8 in Laboratory Techniques inBiochemistry and Molecular Biology, Vol. 24: Hybridization With NucleicAcid Probes, P. Tijssen, ed. Elsevier, N.Y., (1993)).

[0158] The method may or may not further comprise a non-bound labelremoval step prior to the detection step, depending on the particularlabel employed on the target nucleic acid. For example, in certain assayformats (e.g., “homogenous assay formats”) a detectable signal is onlygenerated upon specific binding of target to probe. As such, in theseassay formats, the hybridization pattern may be detected without anon-bound label removal step. In other embodiments, the label employedwill generate a signal whether or not the target is specifically boundto its probe. In such embodiments, the non-bound labeled target isremoved from the support surface. One means of removing the non-boundlabeled target is to perform the well known technique of washing, wherea variety of wash solutions and protocols for their use in removingnon-bound label are known to those of skill in the art and may be used.Alternatively, non-bound labeled target can be removed byelectrophoretic means.

[0159] Where all of the target sequences are detected using the samelabel, different arrays will be employed for each physiological sourceor time point (where different could include using the same array atdifferent times). The above methods can be varied to provide formultiplex analysis, by employing different and distinguishable labelsfor the different target populations (representing each of the differentphysiological sources or time points being assayed). According to thismultiplex method, the same array is used at the same time for each ofthe different target populations.

[0160] In another embodiment, hybridization is monitored in real timeusing a charge-coupled device (CCD) imaging camera (Guschin et al.(1997) Anal. Biochem. 250:203). Synthesis of arrays on optical fibrebundles allows easy and sensitive reading (Healy et al. (1997) Anal.Biochem. 251:270). In another embodiment, real time hybridizationdetection is carried out on microarrays without washing using evanescentwave effect that excites only fluorophores that are bound to the surface(see, e.g., Stimpson et al. (1995) PNAS 92:6379).

[0161] (v) Detection of Hybridization and Analysis of Results

[0162] The above steps result in the production of hybridizationpatterns of target nucleic acid on the array surface. These patterns maybe visualized or detected in a variety of ways, with the particularmanner of detection being chosen based on the particular label of thetarget nucleic acid. Representative detection means includescintillation counting, autoradiography, fluorescence measurement,colorimetric measurement, light emission measurement, light scattering,and the like.

[0163] One method of detection includes an array scanner that iscommercially available from Affymetrix (Santa Clara, Calif.), e.g., the417™ Arrayer, the 418™ Array Scanner, or the Agilent GeneArray™ Scanner.This scanner is controlled from the system computer with a Windows^(R)interface and easy-to-use software tools. The output is a 16-bit.tiffile that can be directly imported into or directly read by a variety ofsoftware applications. Preferred scanning devices are described in,e.g., U.S. Pat. Nos. 5,143,854 and 5,424,186.

[0164] When fluorescently labeled probes are used, the fluorescenceemissions at each site of a transcript array can be detected by scanningconfocal laser microscopy. In one embodiment, a separate scan, using theappropriate excitation line, is carried out for each of the twofluorophores used. Alternatively, a laser can be used that allowssimultaneous specimen illumination at wavelengths specific to the twofluorophores and emissions from the two fluorophores can be analyzedsimultaneously (see Shalon et al., 1996, A DNA microarray system foranalyzing complex DNA samples using two-color fluorescent probehybridization, Genome Research 6:639-645). In a preferred embodiment,the arrays are scanned with a laser fluorescent scanner with a computercontrolled X-Y stage and a microscope objective. Sequential excitationof the two fluorophores can be achieved with a multi-line, mixed gaslaser and the emitted light is split by wavelength and detected with twophotomultiplier tubes. In one embodiment in which fluorescent targetnucleic acids are used, the arrays may be scanned using lasers to excitefluorescently labeled targets that have hybridized to regions of probearrays, which can then be imaged using charged coupled devices (“CCDs”)for a wide field scanning of the array. Fluorescence laser scanningdevices are described, e.g., in Schena et al., 1996, Genome Res.6:639-645. Alternatively, the fiber-optic bundle described by Fergusonet al., 1996, Nature Biotech. 14:1681-1684, may be used to monitor mRNAabundance levels.

[0165] Following the data gathering operation, the data will typicallybe reported to a data analysis operation. To facilitate the sampleanalysis operation, the data obtained by the reader from the device willtypically be analyzed using a digital computer. Typically, the computerwill be appropriately programmed for receipt and storage of the datafrom the device, as well as for analysis and reporting of the datagathered, e.g., subtrackion of the background, deconvolution multi-colorimages, flagging or removing artifacts, verifying that controls haveperformed properly, normalizing the signals, interpreting fluorescencedata to determine the amount of hybridized target, normalization ofbackground and single base mismatch hybridizations, and the like. In apreferred embodiment, a system comprises a search function that allowsone to search for specific patterns, e.g., patterns relating todifferential gene expression of genes which are up- or down-regulatedduring bone or cartilage formation. A system preferably allows one tosearch for patterns of gene expression between more than two samples.

[0166] A desirable system for analyzing data is a general and flexiblesystem for the visualization, manipulation, and analysis of geneexpression data. Such a system preferably includes a graphical userinterface for browsing and navigating through the expression data,allowing a user to selectively view and highlight the genes of interest.The system also preferably includes sort and search functions and ispreferably available for general users with PC, Mac or Unixworkstations. Also preferably included in the system are clusteringalgorithms that are qualitatively more efficient than existing ones. Theaccuracy of such algorithms is preferably hierarchically adjustable sothat the level of detail of clustering can be systematically refined asdesired.

[0167] Various algorithms are available for analyzing the geneexpression profile data, e.g., the type of comparisons to perform. Incertain embodiments, it is desirable to group genes that areco-regulated. This allows the comparison of large numbers of profiles. Apreferred embodiment for identifying such groups of genes involvesclustering algorithms (for reviews of clustering algorithms, see, e.g.,Fukunaga, 1990, Statistical Pattern Recognition, 2nd Ed., AcademicPress, San Diego; Everitt, 1974, Cluster Analysis, London: HeinemannEduc. Books; Hartigan, 1975, Clustering Algorithms, New York: Wiley;Sneath and Sokal, 1973, Numerical Taxonomy, Freeman; Anderberg, 1973,Cluster Analysis for Applications, Academic Press: New York).

[0168] Clustering analysis is useful in helping to reduce complexpatterns of thousands of time curves into a smaller set ofrepresentative clusters. Some systems allow the clustering and viewingof genes based on sequences. Other systems allow clustering based onother characteristics of the genes, e.g., their level of expression(see, e.g., U.S. Pat. No. 6,203,987). Other systems permit clustering oftime curves (see, e.g. U.S. Pat. No. 6,263,287). Cluster analysis can beperformed using the hclust routine (see, e.g., “hclust” routine from thesoftware package S-Plus, MathSoft, Inc., Cambridge, Mass.).

[0169] In some specific embodiments, genes are grouped according to thedegree of co-variation of their transcription, presumably co-regulation,as described in U.S. Pat. No. 6,203,987. Groups of genes that haveco-varying transcripts are termed “genesets.” Cluster analysis or otherstatistical classification methods can be used to analyze theco-variation of transcription of genes in response to a variety ofperturbations, e.g. caused by a disease or a drug. In one specificembodiment, clustering algorithms are applied to expression profiles toconstruct a “similarity tree” or “clustering tree” which relates genesby the amount of co-regulation exhibited. Genesets are defined on thebranches of a clustering tree by cutting across the clustering tree atdifferent levels in the branching hierarchy.

[0170] In some embodiments, a gene expression profile is converted to aprojected gene expression profile. The projected gene expression profileis a collection of geneset expression values. The conversion isachieved, in some embodiments, by averaging the level of expression ofthe genes within each geneset. In some other embodiments, other linearprojection processes may be used. The projection operation expresses theprofile on a smaller and biologically more meaningful set ofcoordinates, reducing the effects of measurement errors by averagingthem over each cellular constituent sets and aiding biologicalinterpretation of the profile.

[0171] Values that can be compared include gross expression levels;averages of expression levels, e.g., from different experiments,different samples from the same subject or samples from differentsubjects; and ratios of expression levels, e.g., between patients andnormal controls.

[0172] A variety of other statistical methods are available to assessthe degree of relatedness in expression patterns of different genes.Certain statistical methods may be broken into two related portions:metrics for determining the relatedness of the expression pattern of oneor more gene, and clustering methods, for organizing and classifyingexpression data based on a suitable metric (Sherlock, 2000, Curr. Opin.Immunol. 12:201-205; Butte et al., 2000, Pacific Symposium onBiocomputing, Hawaii, World Scientific, p.418-29).

[0173] In one embodiment, Pearson correlation may be used as a metric.In brief, for a given gene, each data point of gene expression leveldefines a vector describing the deviation of the gene expression fromthe overall mean of gene expression level for that gene across allconditions. Each gene's expression pattern can then be viewed as aseries of positive and negative vectors. A Pearson correlationcoefficient can then be calculated by comparing the vectors of each geneto each other. An example of such a method is described in Eisen et al.(1998, supra). Pearson correlation coefficients account for thedirection of the vectors, but not the magnitudes.

[0174] In another embodiment, Euclidean distance measurements may beused as a metric. In these methods, vectors are calculated for each genein each condition and compared on the basis of the absolute distance inmultidimensional space between the points described by the vectors forthe gene.

[0175] In a further embodiment, the relatedness of gene expressionpatterns may be determined by entropic calculations (Butte et al. 2000,supra). Entropy is calculated for each gene's expression pattern. Thecalculated entropy for two genes is then compared to determine themutual information. Mutual information is calculated by subtracting theentropy of the joint gene expression patterns from the entropy forcalculated for each gene individually. The more different two geneexpression patterns are, the higher the joint entropy will be and thelower the calculated mutual information. Therefore, high mutualinformation indicates a non-random relatedness between the twoexpression patterns.

[0176] The different metrics for relatedness may be used in various waysto identify clusters of genes. In one embodiment, comprehensive pairwisecomparisons of entropic measurements will identify clusters of geneswith particularly high mutual information. In preferred embodiments,expression patterns for two genes are correlated if the normalizedmutual information score is greater than or equal to 0.7, and preferablygreater than 0.8, greater than 0.9 or greater than 0.95. In alternativeembodiments, a statistical significance for mutual information may beobtained by randomly permuting the expression measurements 30 times anddetermining the highest mutual information measurement obtained fromsuch random associations. All clusters with a mutual information higherthan can be obtained randomly after 30 permutations are statisticallysignificant. In a further embodiment, expression patterns for two genesare correlated if the correlation coefficient is greater than or equalto 0.8, and preferably greater than 0.85, 0.9 or, most preferablygreater than 0.95.

[0177] In another embodiment, agglomerative clustering methods may beused to identify gene clusters. In one embodiment, Pearson correlationcoefficients or Euclidean metrics are determined for each gene and thenused as a basis for forming a dendrogram. In one example, genes werescanned for pairs of genes with the closest correlation coefficient.These genes are then placed on two branches of a dendrogram connected bya node, with the distance between the depth of the branches proportionalto the degree of correlation. This process continues, progressivelyadding branches to the tree. Ultimately a tree is formed in which genesconnected by short branches represent clusters, while genes connected bylonger branches represent genes that are not clustered together. Thepoints in multidimensional space by Euclidean metrics may also be usedto generate dendrograms.

[0178] In yet another embodiment, divisive clustering methods may beused. For example, vectors are assigned to each gene's expressionpattern, and two random vectors are generated. Each gene is thenassigned to one of the two random vectors on the basis of probability ofmatching that vector. The random vectors are iteratively recalculated togenerate two centroids that split the genes into two groups. This splitforms the major branch at the bottom of a dendrogram. Each group is thenfurther split in the same manner, ultimately yielding a fully brancheddendrogram.

[0179] In a further embodiment, self-organizing maps (SOM) may be usedto generate clusters. In general, the gene expression patterns areplotted in n-dimensional space, using a metric such as the Euclideanmetrics described above. A grid of centroids is then placed onto thendimensional space and the centroids are allowed to migrate towardsclusters of points, representing clusters of gene expression. Finallythe centroids represent a gene expression pattern that is a sort ofaverage of a gene cluster. In certain embodiments, SOM may be used togenerate centroids, and the genes clustered at each centroid may befurther represented by a dendrogram. An exemplary method is described inTamayo et al., 1999, PNAS 96:2907-12. Once centroids are formed,correlation must be evaluated by one of the methods described supra.

[0180] 2.2. Other Methods for Determining Gene Expression Levels

[0181] In certain embodiments, it is sufficient to determine theexpression of one or only a few genes, as opposed to hundreds orthousands of genes. Although microarrays can be used in theseembodiments, various other methods of detection of gene expression areavailable. This section describes a few exemplary methods for detectingand quantifying mRNA or polypeptide encoded thereby. Where the firststep of the methods includes isolation of mRNA from cells, this step canbe conducted as described above. Labeling of one or more nucleic acidscan be performed as described above.

[0182] In one embodiment, mRNA obtained form a sample is reversetranscribed into a first cDNA strand and subjected to PCR, e.g., RT-PCR.House keeping genes, or other genes whose expression does not vary canbe used as internal controls and controls across experiments. Followingthe PCR reaction, the amplified products can be separated byelectrophoresis and detected. By using quantitative PCR, the level ofamplified product will correlate with the level of RNA that was presentin the sample. The amplified samples can also be separated on a agaroseor polyacrylamide gel, transferred onto a filter, and the filterhybridized with a probe specific for the gene of interest. Numeroussamples can be analyzed simultaneously by conducting parallel PCRamplification, e.g., by multiplex PCR.

[0183] A quantitative PCR technique that can be used is based on the useof TaqMan™ probes. Specific sequence detection occurs by amplificationof target sequences in the PE Applied Biosystems 7700 Sequence DetectionSystem in the presence of an oligonucleotide probe labeled at the 5′ and3′ ends with a reporter and quencher fluorescent dye, respectively (FQprobe), which anneals between the two PCR primers. Only specific productwill be detected when the probe is bound between the primers. As PCRamplification proceeds, the 5′-nuclease activity of Taq polymeraseinitially cleaves the reporter dye from the probe. The signal generatedwhen the reporter dye is physically separated from the quencher dye isdetected by measuring the signal with an attached CCD camera. Eachsignal generated equals one probe cleaved which corresponds toamplification of one target strand. PCR reactions may be set up usingthe PE Applied Biosystem TaqMan PCR Core Reagent Kit according to theinstructions supplied. This technique is further described, e.g., inU.S. Pat. No. 6,326,462.

[0184] In another embodiment, mRNA levels is determined by dotblotanalysis and related methods (see, e.g., G. A. Beltz et al., in Methodsin Enzymology, Vol. 100, Part B, R. Wu, L. Grossmam, K. Moldave, Eds.,Academic Press, New York, Chapter 19, pp. 266-308, 1985). In oneembodiment, a specified amount of RNA extracted from cells is blotted(i.e., non-covalently bound) onto a filter, and the filter is hybridizedwith a probe of the gene of interest. Numerous RNA samples can beanalyzed simultaneously, since a blot can comprise multiple spots ofRNA. Hybridization is detected using a method that depends on the typeof label of the probe. In another dotblot method, one or more probes ofone or more genes which are up- or down-regulated during bone orcartilage formation are attached to a membrane, and the membrane isincubated with labeled nucleic acids obtained from and optionallyderived from RNA of a cell or tissue of a subject. Such a dotblot isessentially an array comprising fewer probes than a microarray.

[0185] “Dot blot” hybridization gained wide-spread use, and manyversions were developed (see, e.g., M. L. M. Anderson and B. D. Young,in Nucleic Acid Hybridization-A Practical Approach, B. D. Hames and S.J. Higgins, Eds., IRL Press, Washington D.C., Chapter 4, pp. 73-111,1985).

[0186] Another format, the so-called “sandwich” hybridization, involvescovalently attaching oligonucleotide probes to a solid support and usingthem to capture and detect multiple nucleic acid targets (see, e.g., M.Ranki et al., Gene, 21, pp. 77-85, 1983; A. M. Palva, T. M. Ranki, andH. E. Soderlund, in UK Patent Application GB 2156074A, Oct. 2, 1985; T.M. Ranki and H. E. Soderlund in U.S. Pat. No. 4,563,419, Jan. 7, 1986;A. D. B. Malcolm and J. A. Langdale, in PCT WO 86/03782, Jul. 3, 1986;Y. Stabinsky, in U.S. Pat. No. 4,751,177, Jan. 14, 1988; T. H. Adams etal., in PCT WO 90/01564, Feb. 22, 1990; R. B. Wallace et al. 6 NucleicAcid Res. 11, p. 3543, 1979; and B. J. Connor et al., 80 Proc. Natl.Acad. Sci. USA pp. 278-282, 1983). Multiplex versions of these formatsare called “reverse dot blots.”

[0187] mRNA levels can also be determined by Northern blots. Specificamounts of RNA are separated by gel electrophoresis and transferred ontoa filter which is then hybridized with a probe corresponding to the geneof interest. This method, although more burdensome when numerous samplesand genes are to be analyzed provides the advantage of being veryaccurate.

[0188] A preferred method for high throughput analysis of geneexpression is the serial analysis of gene expression (SAGE) technique,first described in Velculescu et al. (1995) Science 270, 484-487. Amongthe advantages of SAGE is that it has the potential to provide detectionof all genes expressed in a given cell type, provides quantitativeinformation about the relative expression of such genes, permits readycomparison of gene expression of genes in two cells, and yields sequenceinformation that can be used to identify the detected genes. Thus far,SAGE methodology has proved itself to reliably detect expression ofregulated and nonregulated genes in a variety of cell types (Velculescuet al. (1997) Cell 88, 243-251; Zhang et al. (1997) Science 276,1268-1272 and Velculescu et al. (1999) Nat. Genet. 23, 387-388).

[0189] Techniques for producing and probing nucleic acids are furtherdescribed, for example, in Sambrook et al., “Molecular Cloning: ALaboratory Manual” (New York, Cold Spring Harbor Laboratory, 1989).

[0190] Alternatively, the level of expression of one or more genes whichare up- or down-regulated during bone or cartilage formation isdetermined by in situ hybridization. In one embodiment, a tissue sampleis obtained from a subject, the tissue sample is sliced, and in situhybridization is performed according to methods known in the art, todetermine the level of expression of the genes of interest.

[0191] In other methods, the level of expression of a gene is detectedby measuring the level of protein encoded by the gene. This can be done,e.g., by immunoprecipitation, ELISA, or immunohistochemistry using anagent, e.g., an antibody, that specifically detects the protein encodedby the gene. Other techniques include Western blot analysis.Immunoassays are commonly used to quantitate the levels of proteins incell samples, and many other immunoassay techniques are known in theart. The invention is not limited to a particular assay procedure, andtherefore is intended to include both homogeneous and heterogeneousprocedures. Exemplary immunoassays which can be conducted according tothe invention include fluorescence polarization immunoassay (FPIA),fluorescence immunoassay (FIA), enzyme immunoassay (EIA), nephelometricinhibition immunoassay (NIA), enzyme linked immunosorbent assay (ELISA),and radioimmunoassay (RIA). An indicator moiety, or label group, can beattached to the subject antibodies and is selected so as to meet theneeds of various uses of the method which are often dictated by theavailability of assay equipment and compatible immunoassay procedures.General techniques to be used in performing the various immunoassaysnoted above are known to those of ordinary skill in the art.

[0192] In the case of polypeptides which are secreted from cells, thelevel of expression of these polypeptides can be measured in biologicalfluids.

[0193] 2.3. Data Analysis Methods

[0194] Comparison of the expression levels of one or more genes whichare up- or down-regulated in a sample, e.g., of a patient, withreference expression levels, e.g., in normal cells undergoing bone orcartilage formation, is preferably conducted using computer systems. Inone embodiment, one or more expression levels are obtained in two cellsand these two sets of expression levels are introduced into a computersystem for comparison. In a preferred embodiment, one set of one or moreexpression levels is entered into a computer system for comparison withvalues that are already present in the computer system, or incomputer-readable form that is then entered into the computer system.

[0195] In one embodiment, the invention provides a computer readableform of the gene expression profile data of the invention, or of valuescorresponding to the level of expression of at least one gene which isup- or down-regulated during bone or cartilage formation. The values canbe mRNA expression levels obtained from experiments, e.g., microarrayanalysis. The values can also be mRNA levels normalized relative to areference gene whose expression is constant in numerous cells undernumerous conditions, e.g., GAPDH. In other embodiments, the values inthe computer are ratios of, or differences between, normalized ornon-normalized mRNA levels in different samples.

[0196] The computer readable medium may comprise values of at least 2,at least 3, at least 5, 10, 20, 50, 100, 200, 500 or more genes, e.g.,genes listed in Tables 1, 2, 5, 6 and/or 7. In a preferred embodiment,the computer readable medium comprises at least one expression profile.

[0197] Gene expression data can be in the form of a table, such as anExcel table. The data can be alone, or it can be part of a largerdatabase, e.g., comprising other expression profiles, e.g., publiclyavailable database. The computer readable form can be in a computer. Inanother embodiment, the invention provides a computer displaying thegene expression profile data.

[0198] Although the invention provides methods in which the level ofexpression of a single gene can be compared in two or more cells ortissue samples, in a preferred embodiment, the level of expression of aplurality of genes is compared. For example, the level of expression ofat least 2, at least 3, at least 5, 10, 20, 50, 100, 200, 500 or moregenes, e.g., genes listed in Tables 1, 2, 5, 6 and/or 7 can be compared.In a preferred embodiment, expression profiles are compared.

[0199] In one embodiment, the invention provides a method fordetermining the similarity between the level of expression of one ormore genes which are up- or down-regulated during bone or cartilageformation in a first cell, e.g., a cell of a subject, and that in asecond cell. The method preferably comprises obtaining the level ofexpression of one or more genes which are up- or down-regulated duringbone or cartilage formation in a first cell and entering these valuesinto a computer comprising (i) a database including records comprisingvalues corresponding to levels of expression of one or more genes whichare up- or down-regulated during bone or cartilage formation in a secondcell, and (ii) processor instructions, e.g., a user interface, capableof receiving a selection of one or more values for comparison purposeswith data that is stored in the computer. The computer may furthercomprise a means for converting the comparison data into a diagram orchart or other type of output.

[0200] In another embodiment, values representing expression levels ofone or more genes which are up- or down-regulated during bone orcartilage formation are entered into a computer system that comprisesone or more databases with reference expression levels obtained frommore than one cell. For example, the computer may comprise expressiondata of diseased, e.g., bone or cartilage cells of an osteoporosispatient, and normal cells. The computer may also comprise expressiondata of genes at different time points during bone or cartilageformation, e.g., the data set forth in Tables 1, 2, 5, 6 and/or 7.Instructions are provided to the computer, and the computer is capableof comparing the data entered with the data in the computer to determinewhether the data entered is more similar to one or the other geneexpression data stored in the computer.

[0201] In another embodiment, the computer comprises values ofexpression levels in cells of subjects at different stages of a diseaserelating to bone or cartilage formation or resorption, and the computeris capable of comparing expression data entered into the computer withthe data stored, and produce results indicating to which of theexpression data in the computer, the one entered is most similar, suchas to determine the stage of the disease in the subject.

[0202] In yet another embodiment, the reference expression data in thecomputer are expression data from cells of one or more subjects having adisease relating to bone or cartilage formation or resorption, whichcells are treated in vivo or in vitro with a drug used for therapy ofthe disease. Upon entering of expression data of a cell of a subjecttreated in vitro or in vivo with the drug, the computer is instructed tocompare the data entered with the data in the computer, and to provideresults indicating whether the expression data input into the computerare more similar to those of a cell of a subject that is responsive tothe drug or more similar to those of a cell of a subject that is notresponsive to the drug. Thus, the results indicate whether the subjectis likely to respond to the treatment with the drug or unlikely torespond to it.

[0203] The reference expression data may also be from cells of subjectsresponding or not responding to several different treatments, and thecomputer system indicates a preferred treatment for the subject.Accordingly, the invention provides a method for selecting a therapy fora patient having a disease relating to bone or cartilage formation orresorption, the method comprising: (i) providing the level of expressionof one or more genes which are up- or down-regulated during bone orcartilage formation in a diseased cell of the patient; (ii) providing aplurality of reference expression levels, each associated with atherapy, wherein the subject expression levels and each referenceexpression level has a plurality of values, each value representing thelevel of expression of a gene that is up- or down-regulated during boneor cartilage formation; and (iii) selecting the reference expressionlevels most similar to the subject expression levels, to thereby selecta therapy for said patient. In a preferred embodiment step (iii) isperformed by a computer. The most similar reference profile may beselected by weighing a comparison value of the plurality using a weightvalue associated with the corresponding expression data.

[0204] In one embodiment, the invention provides a system that comprisesa means for receiving gene expression data for one or a plurality ofgenes; a means for comparing the gene expression data from each of saidone or plurality of genes to a common reference frame; and a means forpresenting the results of the comparison. This system may furthercomprise a means for clustering the data.

[0205] In another embodiment, the invention provides a computer programfor analyzing gene expression data comprising (i) a computer code thatreceives as input gene expression data for a plurality of genes and (ii)a computer code that compares said gene expression data from each ofsaid plurality of genes to a common reference frame.

[0206] The invention also provides a machine-readable orcomputer-readable medium including program instructions for performingthe following steps: (i) comparing a plurality of values correspondingto expression levels of one or more genes which are up- ordown-regulated during bone or cartilage formation in a query cell with adatabase including records comprising reference expression of one ormore reference cells and an annotation of the type of cell; and (ii)indicating to which cell the query cell is most similar based onsimilarities of expression levels.

[0207] The relative levels of expression, e.g., abundance of an mRNA, intwo biological samples can be scored as a perturbation (relativeabundance difference) or as not perturbed (i.e., the relative abundanceis the same). For example, a perturbation can be a difference inexpression levels between the two sources of RNA of at least a factor ofabout 25% (RNA from one source is 25% more abundant in one source thanthe other source), more usually about 50%, even more often by a factorof about 2 (twice as abundant), 3 (three times as abundant) or 5 (fivetimes as abundant). Perturbations can be used by a computer forcalculating and expressing comparisons.

[0208] Preferably, in addition to identifying a perturbation as positiveor negative, it is advantageous to determine the magnitude of theperturbation. This can be carried out, as noted above, by calculatingthe ratio of the emission of the two fluorophores used for differentiallabeling, or by analogous methods that will be readily apparent to thoseof skill in the art.

[0209] The computer readable medium may further comprise a pointer to adescriptor of the level of expression or expression profile, e.g., fromwhich source it was obtained, e.g., from which patient it was obtained.A descriptor can reflect the stage of a disease, the therapy that apatient is undergoing or any other descriptions of the source ofexpression levels.

[0210] In operation, the means for receiving gene expression data, themeans for comparing the gene expression data, the means for presenting,the means for normalizing, and the means for clustering within thecontext of the systems of the present invention can involve a programmedcomputer with the respective functionalities described herein,implemented in hardware or hardware and software; a logic circuit orother component of a programmed computer that performs the operationsspecifically identified herein, dictated by a computer program; or acomputer memory encoded with executable instructions representing acomputer program that can cause a computer to function in the particularfashion described herein.

[0211] Those skilled in the art will understand that the systems andmethods of the present invention may be applied to a variety of systems,including IBM-compatible personal computers running MS-DOS or MicrosoftWindows.

[0212] The computer may have internal components linked to externalcomponents. The internal components may include a processor elementinterconnected with a main memory. The computer system can be an IntelPentium®-based processor of 200 MHz or greater clock rate and with 32 MBor more of main memory. The external component may comprise a massstorage, which can be one or more hard disks (which are typicallypackaged together with the processor and memory). Such hard disks aretypically of 1 GB or greater storage capacity. Other external componentsinclude a user interface device, which can be a monitor, together withan inputing device, which can be a “mouse”, or other graphic inputdevices, and/or a keyboard. A printing device can also be attached tothe computer.

[0213] Typically, the computer system is also linked to a network link,which can be part of an Ethernet link to other local computer systems,remote computer systems, or wide area communication networks, such asthe Internet. This network link allows the computer system to share dataand processing tasks with other computer systems.

[0214] Loaded into memory during operation of this system are severalsoftware components, which are both standard in the art and special tothe instant invention. These software components collectively cause thecomputer system to function according to the methods of this invention.These software components are typically stored on a mass storage. Asoftware component represents the operating system, which is responsiblefor managing the computer system and its network interconnections. Thisoperating system can be, for example, of the Microsoft Windows' family,such as Windows 95, Windows 98, or Windows NT. A software componentrepresents common languages and functions conveniently present on thissystem to assist programs implementing the methods specific to thisinvention. Many high or low level computer languages can be used toprogram the analytic methods of this invention. Instructions can beinterpreted during run-time or compiled. Preferred languages includeC/C++, and JAVA®. Most preferably, the methods of this invention areprogrammed in mathematical software packages which allow symbolic entryof equations and high-level specification of processing, includingalgorithms to be used, thereby freeing a user of the need toprocedurally program individual equations or algorithms. Such packagesinclude Matlab from Mathworks (Natick, Mass.), Mathematica from WolframResearch (Champaign, Ill.), or S-Plus from Math Soft (Cambridge, Mass.).Accordingly, a software component represents the analytic methods ofthis invention as programmed in a procedural language or symbolicpackage. In a preferred embodiment, the computer system also contains adatabase comprising values representing levels of expression of one ormore genes which are up- or down-regulated during bone or cartilageformation. The database may contain one or more expression profiles ofgenes which are up- or down-regulated during bone or cartilage formationin different cells.

[0215] In an exemplary implementation, to practice the methods of thepresent invention, a user first loads expression data into the computersystem. These data can be directly entered by the user from a monitorand keyboard, or from other computer systems linked by a networkconnection, or on removable storage media such as a CD-ROM or floppydisk or through the network. Next the user causes execution ofexpression profile analysis software which performs the steps ofcomparing and, e.g., clustering co-varying genes into groups of genes.

[0216] In another exemplary implementation, expression profiles arecompared using a method described in U.S. Pat. No. 6,203,987. A userfirst loads expression profile data into the computer system. Genesetprofile definitions are loaded into the memory from the storage media orfrom a remote computer, preferably from a dynamic geneset databasesystem, through the network. Next the user causes execution ofprojection software which performs the steps of converting expressionprofile to projected expression profiles. The projected expressionprofiles are then displayed.

[0217] In yet another exemplary implementation, a user first leads aprojected profile into the memory. The user then causes the loading of areference profile into the memory. Next, the user causes the executionof comparison software which performs the steps of objectively comparingthe profiles.

[0218] 3. Exemplary Diagnostic and Prognostic Compositions and Devicesof the Invention

[0219] Any composition and device (e.g., an array or microarray) for usein the above-described methods are within the scope of the invention.

[0220] In one embodiment, the invention provides a compositioncomprising a plurality of detection agents for detecting expression ofgenes which are up- or down-regulated during bone or cartilageformation. In a preferred embodiment, the composition comprises at least2, preferably at least 3, 5, 10, 20, 50, or 100 different detectionagents, such as to genes listed in Tables 1, 2, 5, 6 and/or 7. Incertain embodiments, the composition comprises at most about 1000, 500,300, 100, 50, 30, 10, 5 or 3 detection agents. Certain composition maycomprise no more than about 1, 2, 3, 5, or 10 detection agents of geneswhich are not listed in Tables 1, 2, 5, 6 and/or 7. In certaincompositions, less than about 1%, 3%, 5%, 10%, 30% or 50% of thedetection agents are to genes that are not listed in Tables 1, 2, 5, 6and/or 7. A detection agent can be a nucleic acid probe, e.g., DNA orRNA, or it can be a polypeptide, e.g., as antibody that binds to thepolypeptide encoded by a gene that is up- or down-regulated during boneor cartilage formation. The probes can be present in equal amount or indifferent amounts in the solution.

[0221] A nucleic acid probe can be at least about 10 nucleotides long,preferably at least about 15, 20, 25, 30, 50, 100 nucleotides or more,and can comprise the full length gene. Preferred probes are those thathybridize specifically to genes listed in any of Tables 1, 2, 5, 6and/or 7. If the nucleic acid is short (i.e., 20 nucleotides or less),the sequence is preferably perfectly complementary to the target gene(i.e., a gene that is up- or down-regulated during bone or cartilageformation), such that specific hybridization can be obtained. However,nucleic acids, even short ones that are not perfectly complementary tothe target gene can also be included in a composition of the invention,e.g., for use as a negative control. Certain compositions may alsocomprise nucleic acids that are complementary to, and capable ofdetecting, an allele of a gene.

[0222] In a preferred embodiment, the invention provides nucleic acidswhich hybridize under high stringency conditions of 0.2 to 1×SSC at 65°C. followed by a wash at 0.2×SSC at 65° C. to genes which are up- ordown-regulated during bone or cartilage formation. In anotherembodiment, the invention provides nucleic acids which hybridize underlow stringency conditions of 6×SSC at room temperature followed by awash at 2×SSC at room temperature. Other nucleic acids probes hybridizeto their target in 3×SSC at 40 or 50° C., followed by a wash in 1 or2×SSC at 20, 30, 40, 50, 60, or 65° C.

[0223] Nucleic acids which are at least about 80%, preferably at leastabout 90%, even more preferably at least about 95% and most preferablyat least about 98% identical to genes which are up- or down-regulatedduring bone or cartilage formation or cDNAs thereof, complementsthereof, fragments and variants are also within the scope of theinvention.

[0224] Nucleic acid probes can be obtained by, e.g., polymerase chainreaction (PCR) amplification of gene segments from genomic DNA, cDNA(e.g., by RT-PCR), or cloned sequences. PCR primers are chosen, based onthe known sequence of the genes or cDNA, that result in amplification ofunique fragments. Computer programs can be used in the design of primerswith the required specificity and optimal amplification properties. See,e.g., Oligo version 5.0 (National Biosciences). Factors which apply tothe design and selection of primers for amplification are described, forexample, by Rylchik, W. (1993) “Selection of Primers for PolymeraseChain Reaction,” in Methods in Molecular Biology, Vol. 15, White B. ed.,Humana Press, Totowa, N.J. Sequences can be obtained from GenBank orother public sources.

[0225] Oligonucleotides of the invention may be synthesized by standardmethods known in the art, e.g. by use of an automated DNA synthesizer(such as are commercially available from Biosearch, Applied Biosystems,etc.). As examples, phosphorothioate oligonucleotides may be synthesizedby the method of Stein et al. (1988, Nucl. Acids Res. 16: 3209),methylphosphonate oligonucleotides can be prepared by use of controlledpore glass polymer supports (Sarin et al., 1988, Proc. Nat. Acad. Sci.U.S.A. 85: 7448-7451), etc. In another embodiment, the oligonucleotideis a 2′-O-methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res. 15:6131-6148), or a chimeric RNA-DNA analog (Inoue et al., 1987, FEBS Lett.215: 327-330).

[0226] “Rapid amplification of cDNA ends,” or RACE, is a PCR method thatcan be used for amplifying cDNAs from a number of different RNAs. ThecDNAs may be ligated to an oligonucleotide linker and amplified by PCRusing two primers. One primer may be based on sequence from the instantnucleic acids, for which full length sequence is desired, and a secondprimer may comprise a sequence that hybridizes to the oligonucleotidelinker to amplify the cDNA. A description of this method is reported inPCT Pub. No. WO 97/19110.

[0227] In another embodiment, the invention provides a compositioncomprising a plurality of agents which can detect a polypeptide encodedby a gene that is up- or down-regulated during bone or cartilageformation. An agent can be, e.g., an antibody. Antibodies topolypeptides described herein can be obtained commercially, or they canbe produced according to methods known in the art.

[0228] The probes can be attached to a solid support, such as paper,membranes, filters, chips, pins or glass slides, or any otherappropriate substrate, such as those further described herein. Forexample, probes of genes which are up- or down-regulated during bone orcartilage formation can be attached covalently or non covalently tomembranes for use, e.g., in dotblots, or to solids such as to createarrays, e.g., microarrays. Exemplary solid surfaces, e.g., arrays,comprise probes corresponding to all or a portion of the genes listed inTables 1, 2, 5, 6 and/or 7. Solid surfaces may comprise at least about1, 2, 3, 5, 10, 20, 30, or 100 probes corresponding to genes listed inTables 1, 2, 5, 6 and/or 7. In certain embodiments, solid surfacescomprise less than about 1, 2, 3, 5, 10, 20, 30, or 100 probescorresponding to genes that are not listed in Tables 1, 2, 5, 6 and/or7. In certain solid surfaces, less than about 1%, 2%, 3%, 5%, 10%, 20%,30%, or 50% of the probes are probes that correspond to genes that arenot listed in any of Tables 1, 2, 5, 6 and/or 7.

[0229] The invention also provides computer-readable media and computerscomprising expression values of all or a portion of the genes set forthin Tables 1, 2, 5, 6 and/or 7 during bone and cartilage development,such as the values set forth in Tables 1, 2, 5, 6 and/or 7. The mediaand computers may comprise at least about 1, 2, 3, 5, 10, 20, 30, or 100values of genes listed in Tables 1, 2, 5, 6 and/or 7. In certainembodiments, media and computers comprise less than about 1, 2, 3, 5,10, 20, 30, or 100 values of genes that are not listed in Tables 1, 2,5, 6 and/or 7. In certain media and computers, less than about 1%, 2%,3%, 5%, 10%, 20%, 30%, or 50% of the values correspond to genes that arenot listed in Tables 1, 2, 5, 6 and/or 7.

[0230] Methods for preparing compositions and devices, e.g., computerreadable media, are also within the scope of the invention.

[0231] 4. Therapeutic Methods and Compositions

[0232] Up- or down-regulation of genes which have been shown to be down-and up-regulated during bone formation, respectively, can be used as atherapeutic method in various situations, e.g., diseases relating tobone and cartilage formation, such as osteodystrophy, osteohypertrophy,osteoblastoma, osteopertrusis, osteogenesis imperfecta, osteoporosis,osteopenia, osteoma and osteoblastoma; inflammatory diseases, such asrheumatoid arthritis and osteoarthritis; periondontal disease or otherteeth related diseases; hyperparathyroidism; hypercalcemia ofmalignancy; Paget's disease; osteolytic lesions produced by bonemetastasis; bone loss due to immobilization or sex hormone deficiency;wound healing and related tissue repair (e.g., burns, incisions andulcers); healing of fractures, e.g., in closed and open fracturereduction; improved fixation of artificial joints; repair of congenital,trauma induced, or oncologic resection induced craniofacial defects;tooth repair processes and plastic, e.g., cosmetic plastic, surgery.

[0233] Accordingly, in certain diseases, e.g., osteoporosis, which canbe treated by stimulating bone or cartilage formation, the inventionprovides methods for stimulating bone or cartilage formation. In otherdiseases, e.g., osteodystrophy, osteohypertrophy, osteoma, osteoblastomaand cancers, which can be treated by inhibiting bone or cartilageformation, the invention provides methods for inhibiting bone orcartilage formation.

[0234] Certain genes have been shown herein to be expressed maximally indifferentiated bone cells (see, e.g., genes represented in bold anditalics in Table 1). Such genes are likely to be markers of osteoclastformation, differentiation or activity. Thus, inhibiting the expressionof one or more of these genes or reducing the activity of level of theprotein encoded thereby, will reduce osteoclast activity, and could thusbe used in treating diseases relating to excessive osteoclast activity,e.g., osteopenia, osteoporosis and erosion associated with arthritis.

[0235] In other embodiments, the invention is used for stimulating invitro formation of bone or cartilage that can then be implanted intosubjects.

[0236] In one embodiment, a therapeutic method includes increasing ordecreasing the level of expression of one or more genes whose expressionis abnormally low or high, respectively, relatively to that in a normalsubject. For example, the invention may comprise first determining thelevel of expression of one or more genes that are up- or down-regulatedduring bone or cartilage formation, e.g., genes in any of the Tablesdescribed herein, and then bringing the level of expression of the geneswhose level of expression differs from the control to about the level inthe control.

[0237] Gene expression may be normalized, i.e., brought to within asimilar level relative to a control, by various ways. For example, geneexpression may be normalized by administering the protein that isencoded by the gene; by administering a nucleic acid encoding theprotein that is encoded by the gene; or by stimulating expression of thegene. Reducing gene expression can be achieved, e.g., by administrationof antisense, siRNA, ribozymes or aptamers directed to the gene orantibodies or other molecules that bind and, e.g., inactivate theprotein encoded by the gene.

[0238] In certain embodiments, osteogenic, cartilage-inducing or boneinducing factors can be co-administered together with a gene-specifictherapeutic to a subject. For example, a growth or differentiationfactor or bone morphogenetic protein, e.g., BMP-2 can beco-administered. Other factors that can be co-administered include thosedescribed in European patent applications 148,155 and 169,016.

[0239] 4.1. Methods for Confirming that Modulation of the Expression ofa Gene Improves a Disease Relating to Bone or Cartilage Formation orResorption

[0240] In one embodiment, the effect of up- or down-regulating the levelof expression of a gene which is down- or up-regulated, respectively, ina cell of a subject having a disease relating to bone or cartilageformation or resorption can be confirmed by phenotypic analysis of thecell characteristic of the disease, in particular by determining whetherthe cell adopts a phenotype that is more reminiscent of that of a normalcell than that of a cell characteristic of the disease relating to boneor cartilage formation or resorption. A “cell characteristic of adisease” also referred to as a “diseased cell” refers to a cell of asubject having a disease, which cell is affected by the disease, and istherefore different from the corresponding cell in a non-diseasedsubject. For example a cell characteristic of cancer is a cancer cell ortumor cell.

[0241] The effect on the cell can also be confirmed by measuring thelevel of expression of one or more genes which are up- or down-regulatedduring bone or cartilage formation, and preferably at least about 10, orat least about 100 genes which are up- or down-regulated during bone orcartilage formation. In a preferred embodiment, the level of expressionof a gene is modulated, and the level of expression of at least one genethat is up- or down-regulated during bone or cartilage formation isdetermined, e.g., by using a microarray having probes to the one or moregenes. If the normalization of expression of the gene results in atleast some normalization of the gene expression profile in the diseasedcell, then normalizing the expression of the gene in the subject havingthe disease is expected to improve the disease. The term “normalizationof the expression of a gene in a diseased cell” refers to bringing thelevel of expression of that gene in the diseased cell to a level that issimilar to that in the corresponding normal cell. “Normalization of thegene expression profile in a diseased cell” refers to bringing theexpression profile in a diseased cell essentially to that in thecorresponding non-diseased cell. If, however, the normalization ofexpression of the gene does not result in at least some normalization ofthe gene expression profile in the diseased cell, normalizing theexpression of the gene in a subject having a disease relating to bone orcartilage formation or resorption is not expected to improve thedisease. In certain embodiments, the expression level of two or moregenes which are up- or down-regulated during bone or cartilage formationis modulated and the effect on the diseased cell is determined.

[0242] A preferred cell for use in these assays is a cell characteristicof a disease relating to bone or cartilage formation or resorption thatcan be obtained from a subject and, e.g., established as a primary cellculture. The cell can be immortalized by methods known in the art, e.g.,by expression of an oncogene or large T antigen of SV40. Alternatively,cell lines corresponding to such a diseased cell can be used. Examplesinclude RAW cells and THPI cells. However, prior to using such celllines, it may be preferably to confirm that the gene expression profileof the cell line corresponds essentially to that of a cellcharacteristic of a disease related to bone or cartilage formation orresorption. This can be done as described in details herein.

[0243] Modulating the expression of a gene in a cell can be achieved,e.g., by contacting the cell with an agent that increases the level ofexpression of the gene or the activity of the polypeptide encoded by thegene. Increasing the level of a polypeptide in a cell can also beachieved by transfecting the cell, transiently or stably, with a nucleicacid encoding the polypeptide. Decreasing the expression of a gene in acell can be achieved by inhibiting transcription or translation of thegene or RNA, e.g., by introducing antisense nucleic acids, ribozymes orsiRNAs into the cells, or by inhibiting the activity of the polypeptideencoded by the gene, e.g., by using antibodies or dominant negativemutants. These methods are further described below in the context oftherapeutic methods.

[0244] A nucleic acid encoding a particular polypeptide can be obtained,e.g., by RT-PCR from a cell that is known to express the gene. Primersfor the RT-PCR can be derived from the nucleotide sequence of the geneencoding the polypeptide. The nucleotide sequence of the gene isavailable, e.g., in GenBank or in the publications. GenBank Accessionnumbers of the genes listed in Tables 1, 2, 5, 6 and/or 7 are providedin the tables. Amplified DNA can then be inserted into an expressionvector, according to methods known in the art and transfected intodiseased cells of a disease related to bone or cartilage formation orresorption. In a control experiment, normal counterpart cells can alsobe transfected. The level of expression of the polypeptide in thetransfected cells can be determined, e.g., by electrophoresis andstaining of the gel or by Western blot using an a agent that binds thepolypeptide, e.g., an antibody. The level of expression of one or moregenes which are up- or down-regulated during bone or cartilage formationcan then be determined in the transfected cells having elevated levelsof the polypeptide. In a preferred embodiment, the level of expressionis determined by using a microarray. For example, RNA is extracted fromthe transfected cells, and used as target DNA for hybridization to amicroarray, as further described herein.

[0245] These assays will allow the identification of genes which are up-or down-regulated during bone or cartilage formation that can be used astherapeutic targets for developing therapeutics for diseases relating tobone or cartilage formation or resorption.

[0246] 4.2. Therapeutic Methods

[0247] 4.2.1. Methods for Reducing Expression of a Gene or the Activityor Level of the Protein Encoded thereby in a Patient

[0248] Genes that are expressed at higher levels in diseased cells ofsubjects having a disease relating to bone or cartilage formation orresorption relative to their expression level in a normal cellundergoing bone or cartilage formation may be used as therapeutictargets for treating the disease. For example, it is possible to treatsuch a disease by decreasing the level of the polypeptides in diseasedcells. Similarly, where bone or cartilage formation is undesired, it maybe inhibited by blocking or reducing the expression of a gene or theactivity or level of the encoded polypeptide that is modulated, e.g.,up-regulated, during normal bone or cartilage formation. Bone andcartilage formation may also be stimulated by blocking or reducing theexpression of a gene or the activity or level of the encoded polypeptidethat is modulated, e.g., down-regulated, during normal bone or cartilageformation.

[0249] (i) Antisense Nucleic Acids

[0250] One method for decreasing the level of expression of a gene is tointroduce into the cell antisense molecules which are complementary toat least a portion of the gene or RNA of the gene. An “antisense”nucleic acid as used herein refers to a nucleic acid capable ofhybridizing to a sequence-specific (e.g., non-poly A) portion of thetarget RNA, for example its translation initiation region, by virtue ofsome sequence complementarity to a coding and/or non-coding region. Theantisense nucleic acids of the invention can be oligonucleotides thatare double-stranded or single-stranded, RNA or DNA or a modification orderivative thereof, which can be directly administered in a controllablemanner to a cell or which can be produced intracellularly bytranscription of exogenous, introduced sequences in controllablequantities sufficient to perturb translation of the target RNA.

[0251] Preferably, antisense nucleic acids are of at least sixnucleotides and are preferably oligonucleotides (ranging from 6 to about200 oligonucleotides). In specific aspects, the oligonucleotide is atleast 10 nucleotides, at least 15 nucleotides, at least 100 nucleotides,or at least 200 nucleotides. The oligonucleotides can be DNA or RNA orchimeric mixtures or derivatives or modified versions thereof,single-stranded or double-stranded. The oligonucleotide can be modifiedat the base moiety, sugar moiety, or phosphate backbone. Theoligonucleotide may include other appending groups such as peptides, oragents facilitating transport across the cell membrane (see, e.g.,Letsinger et al., 1989, Proc. Natl. Acad. Sci. U.S.A. 86: 6553-6556;Lemaitre et al., 1987, Proc. Natl. Acad. Sci. 84: 648-652: PCTPublication No. WO 88/09810, published Dec. 15, 1988),hybridization-triggered cleavage agents (see, e.g., Krol et al., 1988,BioTechniques 6: 958-976) or intercalating agents (see, e.g., Zon, 1988,Pharm. Res. 5: 539-549).

[0252] In a preferred aspect of the invention, an antisenseoligonucleotide is provided, preferably as single-stranded DNA. Theoligonucleotide may be modified at any position on its structure withconstituents generally known in the art. For example, the antisenseoligonucleotides may comprise at least one modified base moiety which isselected from the group including but not limited to 5-fluorouracil,5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine,4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil,5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N-6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, queosine, 2-thiocytosine,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v),5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl)uracil, (acp3)w,and 2,6-diaminopurine.

[0253] In another embodiment, the oligonucleotide comprises at least onemodified sugar moiety selected from the group including, but not limitedto, arabinose, 2-fluoroarabinose, xylulose, and hexose.

[0254] In yet another embodiment, the oligonucleotide comprises at leastone modified phosphate backbone selected from the group consisting of aphosphorothioate, a phosphorodithioate, a phosphoramidothioate, aphosphoramidate, a phosphordiamidate, a methylphosphonate, an alkylphosphotriester, and a formacetal or analog thereof.

[0255] In yet another embodiment, the oligonucleotide is a 2-α-anomericoligonucleotide. An α-anomeric oligonucleotide forms specificdouble-stranded hybrids with complementary RNA in which, contrary to theusual β-units, the strands run parallel to each other (Gautier et al.,1987, Nucl. Acids Res. 15:6625-6641).

[0256] The oligonucleotide may be conjugated to another molecule, e.g.,a peptide, hybridization triggered cross-linking agent transport agent,hybridization-triggered cleavage agent, etc. An antisense molecule canbe a “peptide nucleic acid” (PNA). PNA refers to an antisense moleculeor anti-gene agent which comprises an oligonucleotide of at least about5 nucleotides in length linked to a peptide backbone of amino acidresidues ending in lysine. The terminal lysine confers solubility to thecomposition. PNAs preferentially bind complementary single stranded DNAor RNA and stop transcript elongation, and may be pegylated to extendtheir lifespan in the cell.

[0257] The antisense nucleic acids of the invention comprise a sequencecomplementary to at least a portion of a target RNA species. However,absolute complementarity, although preferred, is not required. Asequence “complementary to at least a portion of an RNA,” as referred toherein, means a sequence having sufficient complementarity to be able tohybridize with the RNA, forming a stable duplex; in the case ofdouble-stranded antisense nucleic acids, a single strand of the duplexDNA may thus be tested, or triplex formation may be assayed. The abilityto hybridize will depend on both the degree of complementarity and thelength of the antisense nucleic acid. Generally, the longer thehybridizing nucleic acid, the more base mismatches with a target RNA itmay contain and still form a stable duplex (or triplex, as the case maybe). One skilled in the art can ascertain a tolerable degree of mismatchby use of standard procedures to determine the melting point of thehybridized complex. The amount of antisense nucleic acid that will beeffective in the inhibiting translation of the target RNA can bedetermined by standard assay techniques.

[0258] The synthesized antisense oligonucleotides can then beadministered to a cell in a controlled manner. For example, theantisense oligonucleotides can be placed in the growth environment ofthe cell at controlled levels where they may be taken up by the cell.The uptake of the antisense oligonucleotides can be assisted by use ofmethods well known in the art.

[0259] In an alternative embodiment, the antisense nucleic acids of theinvention are controllably expressed intracellularly by transcriptionfrom an exogenous sequence. For example, a vector can be introduced invivo such that it is taken up by a cell, within which cell the vector ora portion thereof is transcribed, producing an antisense nucleic acid(RNA) of the invention. Such a vector would contain a sequence encodingthe antisense nucleic acid. Such a vector can remain episomal or becomechromosomally integrated, as long as it can be transcribed to producethe desired antisense RNA. Such vectors can be constructed byrecombinant DNA technology methods standard in the art. Vectors can beplasmid, viral, or others known in the art, used for replication andexpression in mammalian cells. Expression of the sequences encoding theantisense RNAs can be by any promoter known in the art to act in a cellof interest. Such promoters can be inducible or constitutive. Mostpreferably, promoters are controllable or inducible by theadministration of an exogenous moiety in order to achieve controlledexpression of the antisense oligonucleotide. Such controllable promotersinclude the Tet promoter. Other usable promoters for mammalian cellsinclude, but are not limited to: the SV40 early promoter region(Bernoist and Chambon, 1981, Nature 290: 304-310), the promotercontained in the 3′ long terminal repeat of Rous sarcoma virus (Yamamotoet al., 1980, Cell 22: 787-797), the herpes thymidine kinase promoter(Wagner et al., 1981, Proc. Natl. Acad. Sci. U.S.A. 78: 1441-1445), theregulatory sequences of the metallothionein gene (Brinster et al., 1982,Nature 296: 39-42), etc.

[0260] Antisense therapy for a variety of cancers is in clinical phaseand has been discussed extensively in the literature. Reed reviewedantisense therapy directed at the Bcl-2 gene in tumors; genetransfer-mediated overexpression of Bcl-2 in tumor cell lines conferredresistance to many types of cancer drugs. (Reed, J. C., N. C. I. (1997)89:988-990). The potential for clinical development of antisenseinhibitors of ras is discussed by Cowsert, L. M., Anti-Cancer DrugDesign (1997) 12:359-371. Additional important antisense targets includeleukemia (Geurtz, A. M., Anti-Cancer Drug Design (1997) 12:341-358);human C-ref kinase (Monia, B. P., Anti-Cancer Drug Design (1997)12:327-339); and protein kinase C (McGraw et al., Anti-Cancer DrugDesign (1997) 12:315-326.

[0261] (ii) Ribozymes

[0262] In another embodiment, the level of a particular mRNA orpolypeptide in a cell is reduced by introduction of a ribozyme into thecell or nucleic acid encoding such. Ribozyme molecules designed tocatalytically cleave mRNA transcripts can also be introduced into, orexpressed, in cells to inhibit expression of the gene (see, e.g., Sarveret al., 1990, Science 247:1222-1225 and U.S. Pat. No. 5,093,246). Onecommonly used ribozyme motif is the hammerhead, for which the substratesequence requirements are minimal. Design of the hammerhead ribozyme isdisclosed in Usman et al., Current Opin. Struct. Biol. (1996) 6:527-533.Usman also discusses the therapeutic uses of ribozymes. Ribozymes canalso be prepared and used as described in Long et al., FASEB J. (1993)7:25; Symons, Ann. Rev. Biochem. (1992) 61:641; Perrotta et al.,Biochem. (1992) 31:16-17; Ojwang et al., Proc. Natl. Acad. Sci. (USA)(1992) 89:10802-10806; and U.S. Pat. No. 5,254,678. Ribozyme cleavage ofHIV-I RNA is described in U.S. Pat. No. 5,144,019; methods of cleavingRNA using ribozymes is described in U.S. Pat. No. 5,116,742; and methodsfor increasing the specificity of ribozymes are described in U.S. Pat.No. 5,225,337 and Koizumi et al., Nucleic Acid Res. (1989) 17:7059-7071.Preparation and use of ribozyme fragments in a hammerhead structure arealso described by Koizumi et al., Nucleic Acids Res. (1989)17:7059-7071. Preparation and use of ribozyme fragments in a hairpinstructure are described by Chowrira and Burke, Nucleic Acids Res. (1992)20:2835. Ribozymes can also be made by rolling transcription asdescribed in Daubendiek and Kool, Nat. Biotechnol. (1997) 15(3):273-277.

[0263] (iii) siRNAs

[0264] Another method for decreasing or blocking gene expression is byintroducing double stranded small interfering RNAs (siRNAs), whichmediate sequence specific mRNA degradation. RNA interference (RNAi) isthe process of sequence-specific, post-transcriptional gene silencing inanimals and plants, initiated by double-stranded RNA (dsRNA) that ishomologous in sequence to the silenced gene. In vivo, long dsRNA iscleaved by ribonuclease III to generate 21- and 22-nucleotide siRNAs. Ithas been shown that 21-nucleotide siRNA duplexes specifically suppressexpression of endogenous and heterologous genes in different mammaliancell lines, including human embryonic kidney (293) and HeLa cells(Elbashir et al. Nature 2001 ;411(6836):494-8).

[0265] (iv) Triplex Formation

[0266] Gene expression can be reduced by targeting deoxyribonucleotidesequences complementary to the regulatory region of the target gene(i.e., the gene promoter and/or enhancers) to form triple helicalstructures that prevent transcription of the gene in target cells in thebody. (See generally, Helene, C. 1991, Anticancer Drug Des.,6(6):569-84; Helene, C., et al., 1992, Ann, N.Y. Accad. Sci., 660:27-36;and Maher, L. J., 1992, Bioassays 14(12):807-15).

[0267] (v) Aptamers

[0268] In a further embodiment, RNA aptamers can be introduced into orexpressed in a cell. RNA aptamers are specific RNA ligands for proteins,such as for Tat and Rev RNA (Good et al., 1997, Gene Therapy 4: 45-54)that can specifically inhibit their translation.

[0269] (vi) Dominant Negative Mutants

[0270] Another method of decreasing the biological activity of apolypeptide is by introducing into the cell a dominant negative mutant.A dominant negative mutant polypeptide will interact with a moleculewith which the polypeptide normally interacts, thereby competing for themolecule, but since it is biologically inactive, it will inhibit thebiological activity of the polypeptide. A dominant negative mutant canbe created by mutating the substrate-binding domain, the catalyticdomain, or a cellular localization domain of the polypeptide.Preferably, the mutant polypeptide will be overproduced. Point mutationsare made that have such an effect. In addition, fusion of differentpolypeptides of various lengths to the terminus of a protein can yielddominant negative mutants. General strategies are available for makingdominant negative mutants. See Herskowitz, Nature (1987) 329:219-222.

[0271] (vi) Use of Agents Inhibiting Transcription or PolypeptideActivity

[0272] In another embodiment, a compound decreasing the expression ofthe gene of interest or the activity of the polypeptide is administeredto a subject having a disease relating to bone or cartilage formation orresorption, such that the level or activity of the polypeptide in thediseased cells decreases, and the disease is improved. Compounds may beknown in the art or can be identified as further described herein. Forexample, where the gene encodes a polypeptide that is a protease, theactivity of the protease can be inhibited, e.g., by a compound thatbinds an active site of the enzyme, by a compound that inhibits theinteraction of the protease with its target, or by a compound thatdecreases the stability of the protease.

[0273] 4.2.2. Methods for Increasing the Expression of a Gene or theActivity or Level of the Protein Encoded Thereby in a Patient

[0274] Genes which are expressed at lower levels in diseased cells ofsubjects having a disease relating to bone or cartilage formation orresorption relative to their expression level in a normal cellundergoing bone or cartilage formation may be used as therapeutictargets for treating such diseases. For example, it may be possible totreat such a disease by increasing the level of the polypeptides indiseased cells. Similarly, where on wishes to stimulate bone formation,one may increase the level of expression of a gene or the activity orlevel of protein encoded by the gene that is modulated, e.g.,up-regulated, during bone or cartilage formation. If one wishes toinhibit bone or cartilage formation, one may increase the level ofexpression of a gene or the activity or level of protein encoded by thegene that is modulated, e.g., down-regulated, during bone or cartilageformation.

[0275] (i) Administration of a Nucleic Acid Encoding a Polypeptide ofInterest to a Subject

[0276] In one embodiment, a nucleic acid encoding a polypeptide ofinterest, or an equivalent thereof, such as a functionally activefragment of the polypeptide, is administered to a subject, such that thenucleic acid arrives at the site of the diseased cells, traverses thecell membrane and is expressed in the diseased cell.

[0277] A nucleic acid encoding a polypeptide of interest can be obtainedas described herein, e.g., by RT-PCR, or from publicly available DNAclones. It may not be necessary to express the full length polypeptidein a cell of a subject, and a functional fragment thereof may besufficient. Similarly, it is not necessary to express a polypeptidehaving an amino acid sequence that is identical to that of the wild-typepolypeptide. Certain amino acid deletions, additions and substitutionsare permitted, provided that the polypeptide retains most of itsbiological activity. For example, it is expected that polypeptideshaving conservative amino acid substitutions will have the same activityas the polypeptide. Polypeptides that are shorter or longer than thewild-type polypeptide or which contain from one to 20 amino aciddeletions, insertions or substitutions and which have a biologicalactivity that is essentially identical to that of the wild-typepolypeptide are referred to herein as “equivalents of the polypeptide.”Equivalent polypeptides also include polypeptides having an amino acidsequence which is at least 80%, preferably at least about 90%, even morepreferably at least about 95% and most preferably at least 98% identicalor similar to the amino acid sequence of the wild-type polypeptide.

[0278] Determining which portion of the polypeptide is sufficient forimproving a disease relating to bone or cartilage formation or whichpolypeptides derived from the polypeptide are “equivalents” which can beused for treating the disease, can be done in in vitro assays. Forexample, expression plasmids encoding various portions of thepolypeptide can be transfected into cells, e.g., diseased cells ofpatients, and the effect of the expression of the portion of thepolypeptide in the cells can be determined, e.g., by visual inspectionof the phenotype of the cell or by obtaining the expression profile ofthe cell, as further described herein.

[0279] Any means for the introduction of polynucleotides into mammals,human or non-human, may be adapted to the practice of this invention forthe delivery of the various constructs of the invention into theintended recipient. In one embodiment of the invention, the DNAconstructs are delivered to cells by transfection, i.e., by delivery of“naked” DNA or in a complex with a colloidal dispersion system. Acolloidal system includes macromolecule complexes, nanocapsules,microspheres, beads, and lipid-based systems including oil-in-wateremulsions, micelles, mixed micelles, and liposomes. The preferredcolloidal system of this invention is a lipid-complexed orliposome-formulated DNA. In the former approach, prior to formulation ofDNA, e.g., with lipid, a plasmid containing a transgene bearing thedesired DNA constructs may first be experimentally optimized forexpression (e.g., inclusion of an intron in the 5′ untranslated regionand elimination of unnecessary sequences (Felgner, et al., Ann NY AcadSci 126-139, 1995). Formulation of DNA, e.g. with various lipid orliposome materials, may then be effected using known methods andmaterials and delivered to the recipient mammal. See, e.g., Canonico etal, Am J Respir Cell Mol Biol 10:24-29, 1994; Tsan et al, Am J Physiol268; Alton et al., Nat Genet. 5:135-142, 1993 and U.S. Pat. No.5,679,647 by Carson et al.

[0280] The targeting of liposomes can be classified based on anatomicaland mechanistic factors. Anatomical classification is based on the levelof selectivity, for example, organ-specific, cell-specific, andorganelle-specific. Mechanistic targeting can be distinguished basedupon whether it is passive or active. Passive targeting utilizes thenatural tendency of liposomes to distribute to cells of thereticulo-endothelial system (RES) in organs, which contain sinusoidalcapillaries. Active targeting, on the other hand, involves alteration ofthe liposome by coupling the liposome to a specific ligand such as amonoclonal antibody, sugar, glycolipid, or protein, or by changing thecomposition or size of the liposome in order to achieve targeting toorgans and cell types other than the naturally occurring sites oflocalization.

[0281] The surface of the targeted delivery system may be modified in avariety of ways. In the case of a liposomal targeted delivery system,lipid groups can be incorporated into the lipid bilayer of the liposomein order to maintain the targeting ligand in stable association with theliposomal bilayer. Various linking groups can be used for joining thelipid chains to the targeting ligand. Naked DNA or DNA associated with adelivery vehicle, e.g., liposomes, can be administered to several sitesin a subject (see below).

[0282] In a preferred method of the invention, the DNA constructs aredelivered using viral vectors. The transgene may be incorporated intoany of a variety of viral vectors useful in gene therapy, such asrecombinant retroviruses, adenovirus, adeno-associated virus (AAV), andherpes simplex virus-1, or recombinant bacterial or eukaryotic plasmids.While various viral vectors may be used in the practice of thisinvention, AAV- and adenovirus-based approaches are of particularinterest. Such vectors are generally understood to be the recombinantgene delivery system of choice for the transfer of exogenous genes invivo, particularly into humans.

[0283] It is possible to limit the infection spectrum of viruses bymodifying the viral packaging proteins on the surface of the viralparticle (see, for example PCT publications WO93/25234, WO94/06920, andWO94/11524). For instance, strategies for the modification of theinfection spectrum of viral vectors include: coupling antibodiesspecific for cell surface antigens to envelope protein (Roux et al.,(1989) PNAS USA 86:9079-9083; Julan et al., (1992) J. Gen Virol73:3251-3255; and Goud et al., (1983) Virology 163:251-254); or couplingcell surface ligands to the viral envelope proteins (Neda et al., (1991)J. Biol. Chem. 266:14143-14146). Coupling can be in the form of thechemical cross-linking with a protein or other variety (e.g. lactose toconvert the env protein to an asialoglycoprotein), as well as bygenerating fusion proteins (e.g. single-chain antibody/env fusionproteins). This technique, while useful to limit or otherwise direct theinfection to certain tissue types, and can also be used to convert anecotropic vector in to an amphotropic vector.

[0284] The expression of a polypeptide of interest or equivalent thereofin cells of a patient to which a nucleic acid encoding the polypeptidewas administered can be determined, e.g., by obtaining a sample of thecells of the patient and determining the level of the polypeptide in thesample, relative to a control sample. The successful administration to apatient and expression of the polypeptide or an equivalent thereof inthe cells of the patient can be monitored by determining the expressionof at least one gene that is up- or down-regulated during bone orcartilage formation, and preferably by determining an expression profileincluding most of the genes which are up- or down-regulated during boneor cartilage formation, as described herein.

[0285] (ii) Administration of a Polypeptide of Interest to a Subject

[0286] In another embodiment, a polypeptide of interest, or anequivalent or variant thereof, e.g., a functional fragment thereof, isadministered to the subject such that it reaches the diseased cells of adisease related to bone or cartilage formation or resorption, andtraverses the cellular membrane. Polypeptides can be synthesized inprokaryotes or eukaryotes or cells thereof and purified according tomethods known in the art. For example, recombinant polypeptides can besynthesized in human cells, mouse cells, rat cells, insect cells, yeastcells, and plant cells. Polypeptides can also be synthesized in cellfree extracts, e.g., reticulocyte lysates or wheat germ extracts.Purification of proteins can be done by various methods, e.g.,chromatographic methods (see, e.g., Robert K Scopes “ProteinPurification: Principles and Practice” Third Ed. Springer-Verlag, N.Y.1994). In one embodiment, the polypeptide is produced as a fusionpolypeptide comprising an epitope tag consisting of about sixconsecutive histidine residues. The fusion polypeptide can then bepurified on a Ni⁺⁺ column. By inserting a protease site between the tagand the polypeptide, the tag can be removed after purification of thepeptide on the Ni⁺⁺ column. These methods are well known in the art andcommercial vectors and affinity matrices are commercially available.

[0287] Administration of polypeptides can be done by mixing them withliposomes, as described above. The surface of the liposomes can bemodified by adding molecules that will target the liposome to thedesired physiological location.

[0288] In one embodiment, a polypeptide is modified so that its rate oftraversing the cellular membrane is increased. For example, thepolypeptide can be fused to a second peptide which promotes“transcytosis,” e.g., uptake of the peptide by cells. In one embodiment,the peptide is a portion of the HIIV transactivator (TAT) protein, suchas the fragment corresponding to residues 37-62 or 48-60 of TAT,portions which are rapidly taken up by cell in vitro (Green andLoewenstein, (1989) Cell 55:1179-1188). In another embodiment, theinternalizing peptide is derived from the Drosophila antennapediaprotein, or homologs thereof. The 60 amino acid long homeodomain of thehomeo-protein antennapedia has been demonstrated to translocate throughbiological membranes and can facilitate the translocation ofheterologous polypeptides to which it is couples. Thus, polypeptides canbe fused to a peptide consisting of about amino acids 42-58 ofDrosophila antennapedia or shorter fragments for transcytosis. See forexample Derossi et al. (1996) J Biol Chem 271:18188-18193; Derossi etal. (1994) J Biol Chem 269:10444-10450; and Perez et al. (1992) J CellSci 102:717-722.

[0289] (iii) Use of Agents Stimulating Transcription or PolypeptideActivity

[0290] In another embodiment, a pharmaceutical composition comprising acompound that stimulates the level of expression of a gene of interestor the activity of the polypeptide in a cell is administered to asubject, such that the level of expression of the gene or polypeptidelevel or activity in the diseased cells is increased or even restored,and the disease is improving in the subject. Compounds may be known inthe art or can be identified as further described herein. Compounds mayincrease the activity of a polypeptide by stabilizing the polypeptide.

[0291] 4.3. Drug Design and Discovery of Therapeutics

[0292] The invention further provides methods for identifyingtherapeutics that modulate bone and cartilage formation. For example,therapeutics that inhibit bone or cartilage formation can be identifiedby treating precursor cells with an agent, such as a bone mophogeneticprotein, e.g., BMP-2, in the presence or absence of a test compound anddetermining whether bone or cartilage formation is inhibited or not bythe presence of the test compound. The effect on bone or cartilageformation can be measured by determining the level of expression of oneor more genes that are up- or down-regulated during bone or cartilageformation, e.g., genes set forth in Tables 1, 2, 5, 6 and/or 7. Theassay that is described in the Examples can be used in such assays.

[0293] In another embodiment, therapeutics which stimulate boneformation can be identified by contacting precursor cells with a testcompound and determining whether bone or cartilage formation isstimulated in the presence of the test compound. A positive control forthis assay can be cells treated with an agent known to cause bone orcartilage formation or differentiation, such as BMP-2. Alternatively,gene expression levels can be measured over a time course and the levelscompared to those set forth in Tables 1, 2, 5, 6 and/or 7.

[0294] As described above, genes whose modulation of expression improvea disease related to bone or cartilage formation or resorption can beused as targets in drug design and discovery. For example, assays can beconducted to identify molecules that modulate the expression and oractivity of genes which are up- or down-regulated during bone orcartilage formation.

[0295] In one embodiment, the invention provides methods for identifyingan agonist or antagonist of a polypeptide, comprising contacting thepolypeptide with a test compound under essentially physiologicalconditions, and determining whether the test compound binds to thepolypeptide or not. In another embodiment, the invention provides amethod for identifying an agonist or antagonist of a polypeptide,comprising contacting the polypeptide with a test compound underessentially physiological conditions; and determining a biologicalactivity of the polypeptide in the presence of the test compound,wherein a higher or lower biological activity in the presence relativeto the absence of the test compound indicates that the test compound isan agonist or antagonist of the polypeptide. Other assays may be basedon a change in the polypeptide, e.g., a change in its phosphorylationlevel.

[0296] In another embodiment, an agent that modulates the expression ofa gene that is up- or down-regulated during bone or cartilage formationis identified by contacting cells expressing the gene with one or moretest compounds, and monitoring the level of expression of the gene,e.g., by directly or indirectly determining the level of the proteinencoded by the gene. Alternatively, compounds which modulate theexpression of the gene can be identified by conducting assays using thepromoter region of a gene and screening for compounds which modifybinding of proteins to the promoter region. The nucleotide sequence ofthe promoter may be described in a publication or available in GenBank.Alternatively, the promoter region of the gene can be isolated, e.g., byscreening a genomic library with a probe corresponding to the gene. Suchmethods are known in the art.

[0297] Inhibitors of the polypeptide can also be agents which bind tothe polypeptide, and thereby prevent it from functioning normally, orwhich degrades or causes the polypeptide to be degraded. For example,such an agent can be an antibody or derivative thereof which interactsspecifically with the polypeptide. Preferred antibodies are monoclonalantibodies, humanized antibodies, human antibodies, and single chainantibodies. Such antibodies can be prepared and tested as known in theart.

[0298] If a polypeptide of interest binds to another polypeptide, drugscan be developed which modulate the activity of the polypeptide bymodulating its binding to the other polypeptide (referred to herein as“binding partner”). Cell-free assays can be used to identify compoundswhich are capable of interacting with the polypeptide or bindingpartner, to thereby modify the activity of the polypeptide or bindingpartner. Such a compound can, e.g., modify the structure of thepolypeptide or binding partner and thereby effect its activity.Cell-free assays can also be used to identify compounds which modulatethe interaction between the polypeptide and a binding partner. In apreferred embodiment, cell-free assays for identifying such compoundsconsist essentially in a reaction mixture containing the polypeptide anda test compound or a library of test compounds in the presence orabsence of a binding partner. A test compound can be, e.g., a derivativeof a binding partner, e.g., a biologically inactive peptide, or a smallmolecule.

[0299] Accordingly, one exemplary screening assay of the presentinvention includes the steps of contacting the polypeptide or functionalfragment thereof or a binding partner with a test compound or library oftest compounds and detecting the formation of complexes. For detectionpurposes, the molecule can be labeled with a specific marker and thetest compound or library of test compounds labeled with a differentmarker. Interaction of a test compound with a polypeptide or fragmentthereof or binding partner can then be detected by determining the levelof the two labels after an incubation step and a washing step. Thepresence of two labels after the washing step is indicative of aninteraction.

[0300] An interaction between molecules can also be identified by usingreal-time BIA (Biomolecular Interaction Analysis, Pharmacia BiosensorAB) which detects surface plasmon resonance (SPR), an opticalphenomenon. Detection depends on changes in the mass concentration ofmacromolecules at the biospecific interface, and does not require anylabeling of interactants. In one embodiment, a library of test compoundscan be immobilized on a sensor surface, e.g., which forms one wall of amicro-flow cell. A solution containing the polypeptide, functionalfragment thereof, polypeptide analog or binding partner is then flowncontinuously over the sensor surface. A change in the resonance angle asshown on a signal recording, indicates that an interaction has occurred.This technique is further described, e.g., in BIAtechnology Handbook byPharmacia.

[0301] Another exemplary screening assay of the present inventionincludes the steps of (a) forming a reaction mixture including: (i) apolypeptide of interest, (ii) a binding partner, and (iii) a testcompound; and (b) detecting interaction of the polypeptide and thebinding partner. The polypeptide and binding partner can be producedrecombinantly, purified from a source, e.g., plasma, or chemicallysynthesized, as described herein. A statistically significant change(potentiation or inhibition) in the interaction of the polypeptide andbinding partner in the presence of the test compound, relative to theinteraction in the absence of the test compound, indicates a potentialagonist (mimetic or potentiator) or antagonist (inhibitor) of thepolypeptide bioactivity for the test compound. The compounds of thisassay can be contacted simultaneously. Alternatively, the polypeptidecan first be contacted with a test compound for an appropriate amount oftime, following which the binding partner is added to the reactionmixture. The efficacy of the compound can be assessed by generating doseresponse curves from data obtained using various concentrations of thetest compound. Moreover, a control assay can also be performed toprovide a baseline for comparison. In the control assay, isolated andpurified polypeptide or binding partner is added to a compositioncontaining the binding partner or polypeptide, and the formation of acomplex is quantified in the absence of the test compound.

[0302] Complex formation between a polypeptide and a binding partner maybe detected by a variety of techniques. Modulation of the formation ofcomplexes can be quantitated using, for example, detectably labeledproteins such as radiolabeled, fluorescently labeled, or enzymaticallylabeled polypeptides or binding partners, by immunoassay, or bychromatographic detection.

[0303] For processes that rely on immunodetection for quantitating oneof the proteins trapped in the complex, antibodies against the proteincan be used. Alternatively, the protein to be detected in the complexcan be “epitope tagged” in the form of a fusion protein which includes,in addition to the polypeptide sequence, a second polypeptide for whichantibodies are readily available (e.g. from commercial sources). Forinstance, the GST fusion proteins described above can also be used forquantification of binding using antibodies against the GST moiety. Otheruseful epitope tags include myc-epitopes (e.g., see Ellison et al.(1991) J Biol Chem 266:21150-21157) which includes a 10-residue sequencefrom c-myc, as well as the pFLAG system (International Biotechnologies,Inc.) or the pEZZ-protein A system (Pharmacia, N.J.).

[0304] Similar assays can be used to identify compounds that bind aprotein of interest and thereby inhibit the activity of the protein.

[0305] In another embodiment, drugs are designed or optimized bymonitoring the level of expression of a plurality of genes, e.g., withmicroarrays. In one embodiment, compounds are screened by comparing theexpression level of one or more genes which are up- or down-regulated(e.g., expression profile) during bone or cartilage formation in a cell,e.g., a cell characteristic of a disease relating to bone or cartilageformation or resorption treated with a drug, relative to theirexpression in a reference cell, e.g., a normal cell. Optionally theexpression profile is also compared to that of a cell characteristic ofthe disease. The comparisons are preferably done by introducing the geneexpression profile data of the cell treated with the drug into acomputer system comprising reference gene expression profiles which arestored in a computer readable form, using appropriate algorithms. Testcompounds will be screened for those which alter the level of expressionof genes, so as to bring them to a level that is similar to that in areference or normal cell of the same type as a cell characteristic ofthe disease. Compounds which are capable of normalizing the expressionof at least about 10%, preferably at least about 20%, 50%, 70%, 80% or90% of the genes which are up- or down-regulated during bone orcartilage formation, are candidate therapeutics.

[0306] The efficacy of the compounds can then be tested in additional invitro assays and in vivo, in animal models, such as the one described inthe Examples. The test compound is administered to the test animal andone or more symptoms of the disease are monitored for improvement of thecondition of the animal. Expression of one or more genes which are up-or down-regulated during bone or cartilage formation can also bemeasured before and after administration of the test compound to theanimal. A normalization of the expression of one or more of these genesis indicative of the efficiency of the compound for treating a diseaserelating to bone or cartilage formation or resorption.

[0307] The toxicity, such as resulting from a stress-related response,of a candidate therapeutic compound can be evaluated, e.g., bydetermining whether it induces the expression of genes known to beassociated with a toxic response. Expression of such toxicity relatedgenes may be determined in different cell types, preferably those thatare known to express the genes. In a preferred method, microarrays areused for detecting changes in gene expression of genes known to beassociated with a toxic response. Changes in gene expression may be amore sensitive marker of human toxicity than routine preclinical safetystudies. It was shown, e.g., that a drug which was found not be to toxicin laboratory animals was toxic when administered to humans. When geneprofiling was studied in cells contacted with the drug, however, it wasfound that a gene, whose expression is known to correlate to livertoxicity, was expressed (see below).

[0308] Such microarrays will comprise genes which are modulated inresponse to toxicity or stress. An exemplary array that can be used forthat purpose is the Affymetrix Rat Toxicology U34 array, which containsprobes of the following genes: metabolism enzymes, e.g., CYP450s,acetyltransferases, and sulfotransferases; growth factors and theirreceptors, e.g., IGFs, interleukins, NGTs, TGFs, and VEGT; kinases andphosphatases, e.g., lipid kinases, MAFKs, and stress-activated kinases;nuclear receptors, e.g., retinoic acid, retinoid X and PPARs;transcription factors, e.g., oncogenes, STATs, NF-kB, and zinc fingerproteins; apoptosis genes, e.g., Bcl-2 genes, Bad, Bax, Caspases andFas; stress response genes, e.g., heat-shock proteins and drugtransporters; membrane proteins, e.g., gap-junction proteins andselectins; and cell-cycle regulators, e.g., cyclins andcyclin-associated proteins. Other genes included in the microarrays areonly known because they contain the nucleotide sequence of an EST andbecause they have a connection with toxicity.

[0309] In one embodiment, a drug of interest is incubated with a cell,e.g., a cell in culture, the RNA is extracted, and expression of genesis analyzed with an array containing genes which have been shown to beup- or down-regulated in response to certain toxins. The results of thehybridization are then compared to databases containing expressionlevels of genes in response to certain known toxins in certainorganisms. For example, the GeneLogic ToxExpress™ database can be usedfor that purpose. The information in this database was obtained in leastin part from the use of the Affymetrix GeneChip® rat and human probearrays with samples treated in vivo or in vitro with known toxins. Thedatabase contains levels of expression of liver genes in response toknown liver toxins. These data were obtained by treating liver samplesfrom rats treated in vivo with known toxins, and comparing the level ofexpression of numerous genes with that in rat or human primaryhepatocytes treated in vitro with the same toxin. Data profiles can beretrieved and analyzed with the GeneExpress™ database tools, which aredesigned for complex data management and analysis. As indicated on theAffymetrix (Santa Clara, Calif.) website, the GeneLogic, Inc.(Gaithersburg, Md.) has preformed proof of concept studies showing thechanges in gene expression levels can predict toxic events that were notidentified by routine preclinical safety testing. GeneLogic tested adrug that had shown no evidence of liver toxicity in rats, but thatlater showed toxicity in humans. The hybridization results using theAffymetrix GeneChip® and GeneExpress™ tools showed that the drug causedabnormal elevations of alanine aminotransferase (ALT), which indicatesliver injury, in half of the patients who had used the drug.

[0310] In one embodiment of the invention, the drug of interest isadministered to an animal, such as a mouse or a rat, at different doses.As negative controls, animals are administered the vehicle alone, e.g.,buffer or water. Positive controls can consist of animals treated withdrugs known to be toxic. The animals can then be sacrificed at differenttimes, e.g., at 3, 6, and 24 hours, after administration of the drug,vehicle alone or positive control drug, mRNA extracted from a sample oftheir liver; and the mRNA analyzed using arrays containing nucleic acidsof genes which are likely to be indicative of toxicity, e.g., theAffymetrix Rat Toxicology U34 assay. The hybridization results can thenbe analyzed using computer programs and databases, as described above.

[0311] In addition, toxicity of a drug in a subject can be predictedbased on the alleles of drug metabolizing genes that are present in asubject. Accordingly, it is known that certain enzymes, e.g., cytochromep450 enzymes, i.e., CYP450, metabolize drugs, and thereby may renderdrugs which are innocuous in certain subjects, toxic in others. Acommercially available array containing probes of different alleles ofsuch drug metabolizing genes can be obtained, e.g., from Affymetrix(Santa Clara, Calif.), under the name of GeneChip® CYP450 assay.

[0312] Thus, a drug for a disease relating to bone or cartilagedevelopment identified as described herein can be optimized by reducingany toxicity it may have. Compounds can be derivatized in vitro usingknown chemical methods and tested for expression of toxicity relatedgenes. The derivatized compounds must also be retested for normalizationof expression levels of genes which are up- or down-regulated duringbone or cartilage formation. For example, the derivatized compounds canbe incubated with diseased cells of a disease relating to bone orcartilage formation or resorption, and the gene expression profiledetermined using microarrays. Thus, incubating cells with derivatizedcompounds and measuring gene expression levels with a microarray thatcontains the genes which are up- or down-regulated during bone orcartilage formation and a microarray containing toxicity related genes,compounds which are effective in treating diseases relating to bone orcartilage formation or resorption and which are not toxic can bedeveloped. Such compounds can further be tested in animal models asdescribed above.

[0313] In another embodiment of the invention, a drug is developed byrational drug design, i.e., it is designed or identified based oninformation stored in computer readable form and analyzed by algorithms.More and more databases of expression profiles are currently beingestablished, numerous ones being publicly available. By screening suchdatabases for the description of drugs affecting the expression of atleast some of the genes which are up- or down-regulated during bone orcartilage formation in a manner similar to the change in gene expressionprofile from a cell characteristic of a disease related to bone orcartilage formation or resorption to that of a normal counterpart cell,compounds can be identified which normalize gene expression in a cellcharacteristic of such a disease. Derivatives and analogues of suchcompounds can then be synthesized to optimize the activity of thecompound, and tested and optimized as described above.

[0314] Compounds identified by the methods described above are withinthe scope of the invention. Compositions comprising such compounds, inparticular, compositions comprising a pharmaceutically efficient amountof the drug in a pharmaceutically acceptable carrier are also provided.Certain compositions comprise one or more active compounds for treatingdiseases relating to bone or cartilage development.

[0315] 4.4. Exemplary Therapeutic Compositions

[0316] Therapeutic compositions include the compounds described herein,e.g., in the context of therapeutic treatments of diseases relating tobone or cartilage formation or resorption. Therapeutic compositions maycomprise one or more nucleic acids encoding a polypeptide characteristicof a disease relating to bone or cartilage formation or resorption, orequivalents thereof. The nucleic acids may be in expression vectors,e.g., viral vectors. Other compositions comprise one or morepolypeptides that are up- or down-regulated during bone or cartilageformation, or equivalents thereof. Yet other compositions comprisenucleic acids encoding antisense RNA, or ribozymes, siRNAs or RNAaptamers. Also within the scope of the invention are compositionscomprising compounds identified by the methods described herein. Thecompositions may comprise pharmaceutically acceptable excipients, andmay be contained in a device for their administration, e.g., a syringe.

[0317] 4.5. Administration of Compounds and Compositions of theInvention

[0318] In a preferred embodiment, the invention provides a method fortreating a subject having a disease relating to bone or cartilageformation or resorption, comprising administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of the invention.

[0319] 4.5.1. Effective Dose

[0320] Compounds of the invention refer to small molecules,polypeptides, peptide mimetics, nucleic acids or any other moleculeidentified as potentially useful for treating diseases relating to boneor cartilage formation or resorption.

[0321] Toxicity and therapeutic efficacy of compounds can be determinedby standard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD50 (The Dose Lethal To 50% Of ThePopulation) and the ED50 (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD50/ED50.Compounds which exhibit large therapeutic indices are preferred. Whilecompounds that exhibit toxic side effects may be used, care should betaken to design a delivery system that targets such compounds to thesite of affected tissue in order to minimize potential damage to healthycells and, thereby, reduce side effects.

[0322] Data obtained from cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For any compound usedin the method of the invention, the therapeutically effective dose canbe estimated initially from cell culture assays. A dose may beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (i.e., the concentration ofthe test compound which achieves a half-maximal inhibition of symptoms)as determined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography.

[0323] 4.5.2. Formulation

[0324] Pharmaceutical compositions for use in accordance with thepresent invention may be formulated in conventional manner using one ormore physiologically acceptable carriers or excipients. Thus, thecompounds and their physiologically acceptable salts and solvates may beformulated for administration by, for example, injection, inhalation orinsufflation (either through the mouth or the nose) or oral, buccal,parenteral or rectal administration. In one embodiment, the compound isadministered locally, at the site where the diseased cells are present,e.g., in bone, cartilage, mesenchymal tissue, muscular tissue or in ajoint.

[0325] The compounds of the invention can be formulated for a variety ofloads of administration, including systemic and topical or localizedadministration. Techniques and formulations generally may be found inRemmington's Pharmaceutical Sciences, Meade Publishing Co., Easton, Pa.For systemic administration, injection is preferred, includingintramuscular, intravenous, intraperitoneal, and subcutaneous. Forinjection, the compounds of the invention can be formulated in liquidsolutions, preferably in physiologically compatible buffers such asHank's solution or Ringer's solution. In addition, the compounds may beformulated in solid form and redissolved or suspended immediately priorto use. Lyophilized forms are also included.

[0326] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets, lozanges, or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulphate). The tablets may be coated by methods well known in theart. Liquid preparations for oral administration may take the form of,for example, solutions, syrups or suspensions, or they may be presentedas a dry product for constitution with water or other suitable vehiclebefore use. Such liquid preparations may be prepared by conventionalmeans with pharmaceutically acceptable additives such as suspendingagents (e.g., sorbitol syrup, cellulose derivatives or hydrogenatededible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueousvehicles (e.g., ationd oil, oily esters, ethyl alcohol or fractionatedvegetable oils); and preservatives (e.g., methyl orpropyl-p-hydroxybenzoates or sorbic acid). The preparations may alsocontain buffer salts, flavoring, coloring and sweetening agents asappropriate. Preparations for oral administration may be suitablyformulated to give controlled release of the active compound.

[0327] For administration by inhalation, the compounds for use accordingto the present invention are conveniently delivered in the form of anaerosol spray presentation from pressurized packs or a nebuliser, withthe use of a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

[0328] The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

[0329] The compounds may also be formulated in rectal compositions suchas suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

[0330] In addition to the formulations described previously, thecompounds may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

[0331] Administration, e.g., systemic administration, can also be bytransmucosal or transdermal means. For transmucosal or transdermaladministration, penetrants appropriate to the barrier to be permeatedare used in the formulation. Such penetrants are generally known in theart, and include, for example, for transmucosal administration bilesalts and fusidic acid derivatives. In addition, detergents may be usedto facilitate permeation. Transmucosal administration may be throughnasal sprays or using suppositories. For topical administration, thecompounds of the invention can be formulated into ointments, salves,gels, or creams as generally known in the art. A wash solution can beused locally to treat an injury or inflammation to accelerate healing.

[0332] In clinical settings, a gene delivery system for a gene ofinterest can be introduced into a patient by any of a number of methods,each of which is familiar in the art. For instance, a pharmaceuticalpreparation of the gene delivery system can be introduced systemically,e.g., by intravenous injection, and specific transduction of the proteinin the target cells occurs predominantly from specificity oftransfection provided by the gene delivery vehicle, cell-type ortissue-type expression due to the transcriptional regulatory sequencescontrolling expression of the receptor gene, or a combination thereof.In other embodiments, initial delivery of the recombinant gene is morelimited with introduction into the subject or animal being quitelocalized. For example, the gene delivery vehicle can be introduced bycatheter (see U.S. Pat. No. 5,328,470) or by stereotactic injection(e.g., Chen et al. (1994) PNAS 91: 3054-3057). A nucleic acid, such asone encoding a polypeptide of interest or homologue thereof can bedelivered in a gene therapy construct by electroporation usingtechniques described, for example, by Dev et al. ((1994) Cancer TreatRev 20:105-115). Gene therapy can be conducted in vivo or ex vivo.

[0333] The pharmaceutical preparation of the gene therapy construct orcompound of the invention can consist essentially of the gene deliverysystem in an acceptable diluent, or can comprise a slow release matrixin which the gene delivery vehicle or compound is imbedded.Alternatively, where the complete gene delivery system can be producedintact from recombinant cells, e.g., retroviral vectors, thepharmaceutical preparation can comprise one or more cells which producethe gene delivery system.

[0334] The compositions may, if desired, be presented in a pack ordispenser device which may contain one or more unit dosage formscontaining the active ingredient. The pack may for example comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.

[0335] The therapeutic method may include administering the compositiontopically, systematically, or locally as an implant or device. Whenadministered, the therapeutic composition for use in this invention is,of course, in a pyrogen-free, physiologically acceptable form. Further,the composition may desirably be encapsulated or injected in a viscousform for delivery to the site of bone, cartilage, tissue damage ordiseased cells. Topical administration may be suitable for wound healingand tissue repair. Therapeutically useful agents other than thegene-specific therapeutics which may also optionally be included in thecomposition as described above, may alternatively or additionally, beadministered simultaneously or sequentially with a composition of theinvention. The compositions of the invention may be employed inassociation with surgery. Preferably for bone and/or cartilageformation, the composition would include a matrix capable of deliveringthe therapeutics to the site of bone and/or cartilage damage or othertarget site, providing a structure for the developing bone and cartilageand optimally capable of being resorbed into the body. Such matrices maybe formed of materials presently in use for other implanted medicalapplications.

[0336] The choice of matrix material may be based on biocompatibility,biodegradability, mechanical properties, cosmetic appearance andinterface properties. The particular application of the compositions ofthe invention will define the appropriate formulation. Potentialmatrices for the compositions may be biodegradable and chemicallydefined calcium sulfate, tricalciumphosphate, hydroxyapatite, polylacticacid, polyglycolic acid and polyanhydrides. Other potential materialsare biodegradable and biologically well defined, such as bone or dermalcollagen. Further matrices are comprised of pure proteins orextracellular matrix components. Other potential matrices arenonbiodegradable and chemically defined, such as sinteredhydroxyapatite, bioglass, aluminates, or other ceramics. Matrices may becomprised of combinations of any of the above mentioned types ofmaterial, such as polylactic acid and hydroxyapatite or collagen andtricalciumphosphate. The bioceramics may be altered in composition, suchas in calcium-aluminate-phosphate and processing to alter pore size,particle size, particle shape, and biodegradability.

[0337] The dosage regimen will be determined by the attending physicianconsidering various factors which modify the action of the therapeutics,e.g. amount of bone weight desired to be formed, the site of bone damageor diseased cells, the condition of the damaged bone, the type ofdisease, the size of a wound, type of damaged tissue, the patient's age,sex, and diet, the severity of any infection, time of administration andother clinical factors. The dosage may vary with the type of matrix usedin the reconstitution and the types of therapeutics in the composition.The addition of other known growth factors, such as BMP-2 and IGF I(insulin like growth factor I), to the final composition, may alsoeffect the dosage. Progress can be monitored by periodic assessment ofbone growth and/or repair, for example, x-rays, histomorphometricdeterminations and tetracycline labeling.

[0338] 5. Exemplary Kits

[0339] The invention further provides kits for determining theexpression level of genes which are up- or down-regulated during bone orcartilage formation or resorption. The kits may be useful foridentifying subjects that are predisposed to developing or who have adisease relating to bone or cartilage formation or resorption, as wellas for identifying and validating therapeutics for such diseases. In oneembodiment, the kit comprises a computer readable medium on which isstored one or more gene expression profiles, e.g., of cellsdifferentiating into bone or cartilage cells, or of diseased cells of adisease relating to bone or cartilage formation or resorption, or atleast values representing levels of expression of one or more geneswhich are up- or down-regulated during bone or cartilage formation. Thecomputer readable medium can also comprise gene expression profiles ofcounterpart normal cells, such as the expression profiles set forth inTables 1, 2, 5, 6 and/or 7; diseased cells treated with a drug, and anyother gene expression profile described herein. The kit can compriseexpression profile analysis software capable of being loaded into thememory of a computer system.

[0340] A kit can comprise a microarray comprising probes of genes whichare up- or down-regulated during bone or cartilage formation. A kit cancomprise one or more probes or primers for detecting the expressionlevel of one or more genes which are up- or down-regulated during boneor cartilage formation and/or a solid support on which probes areattached and which can be used for detecting expression of one or moregenes which are up- or down-regulated during bone or cartilage formationin a sample. A kit may further comprise nucleic acid controls, buffers,and instructions for use.

[0341] Other kits provide compositions for treating a disease relatingto bone or cartilage formation or resorption. For example, a kit maycomprise one or more nucleic acids corresponding to one or more geneswhich are up- or down-regulated during bone or cartilage formation,e.g., for use in treating a patient having a disease relating to bone orcartilage formation or resorption. The nucleic acids can be included ina plasmid or a vector, e.g., a viral vector. Other kits comprise apolypeptide encoded by a gene that is up- or down-regulated during boneor cartilage formation or an antibody to a polypeptide. Yet other kitscomprise compounds identified herein as agonists or antagonists of geneswhich are up- or down-regulated during bone or cartilage formation. Thecompositions may be pharmaceutical compositions comprising apharmaceutically acceptable excipient.

[0342] Yet other kits comprise components for the identification ofdrugs that modulate the activity of a protein encoded by a gene that isup- or down-regulated during bone or cartilage formation. Exemplary kitsmay comprise a polypeptide encoded by a gene or a nucleic acid encodingsuch a polypeptide that is listed in any of the Tables described herein.

[0343] The present invention is further illustrated by the followingexamples which should not be construed as limiting in any way. Thecontents of all cited references including literature references, issuedpatents, published and non published patent applications as citedthroughout this application, as well as those listed below, are herebyexpressly incorporated by reference.

[0344] Bork, P. (1993) FEBS Lett. 327:125-130; Kothapalli, D., et al.(1998) FASEB J. 12:1151-1161; Bond, J. S. and Benyon, R. J. (1995)Protein Sci. 4:1247-1261; Stocker, W., et al. (1995) Protein Sci.4:823-840; Kessler, E., et al. (2001) J. Biol. Chem. 276: 27051-27057;Kessler, E., et al. (1996) Science 271: 360-362; Jakob, M., et al.(2001) J. Cell Biochem. 81: 368-377; Hiraki, Y., et al. (1988) Biochim.Biophys. Acta 969: 91-99; Scott, I. C., et al. (2000) J. Biol. Chem.275: 30504-30511; Hansen, K., et al. (1997) FEBS Lett. 409: 195-200,1997; Hansen, K., et al. (1997) Biochem. Biophys. Res. Commun. 241:355-362, 1997; Jahner, D. and Hunter, T. (1991) Mol. Cell Biol. 11:3682-3690.

[0345] The practice of the present invention will employ, unlessotherwise indicated, conventional techniques of cell biology, cellculture, molecular biology, transgenic biology, microbiology,recombinant DNA, and immunology, which are within the skill of the art.Such techniques are explained fully in the literature. (See, forexample, Molecular Cloning A Laboratory Manual, 2nd Ed., ed. bySambrook, Fritsch and Maniatis (Cold Spring Harbor Laboratory Press:1989); DNA Cloning, Volumes I and II (D. N. Glover ed., 1985);Oligonucleotide Synthesis (M. J. Gait ed., 1984); Mullis et al. U.S.Pat. No. 4,683,195; Nucleic Acid Hybridization (B. D. Hames & S. J.Higgins eds. 1984); Transcription And Translation (B. D. Hames & S. J.Higgins eds. 1984); (R. I. Freshney, Alan R. Liss, Inc., 1987);Immobilized Cells And Enzymes (IRL Press, 1986); B. Perbal, A PracticalGuide To Molecular Cloning (1984); the treatise, Methods In Enzymology(Academic Press, Inc., N.Y.); Gene Transfer Vectors For Mammalian Cells(J. H. Miller and M. P. Calos eds., 1987, Cold Spring HarborLaboratory); Vols. 154 and 155 (Wu et al. eds.), Immunochemical MethodsIn Cell And Molecular Biology (Mayer and Walker, eds., Academic Press,London, 1987); Handbook Of Experimental Immunology, Volumes I-IV (D. M.Weir and C. C. Blackwell, eds., 1986) (Cold Spring Harbor LaboratoryPress, Cold Spring Harbor, N.Y., 1986).

EXAMPLES Example 1

[0346] This Example describes the identification of genes which are up-and down-regulated during hBMP-2 induced ectopic bone formation in mousequadriceps muscles The following animal model of ectopic bone formationwas used. Human BMP-2 (Wyeth Research Division of Wyeth Pharmaceuticals,Inc.) was diluted to a final concentration of 1 mg/ml in formulationbuffer (0.5% sucrose, 2.5% glycine, 5 mM L-glutamic acid, 5 mM NaCl,0.01% polysorbate 80, pH 4.5) (Wyeth Research Division of WyethPharmaceuticals, Inc., MFR00842). Female B6.CB17-Prkdc<SCID>SzJ mice (14weeks of age; Jackson Lab.) were randomly assigned to either a controlor an experimental group. Mice in the control group were injected with50 μl of formulation buffer into the quadriceps muscle of each leg.Similarly, mice in the experimental group were injected with 50 μg ofrecombinant human BMP-2 (hBMP-2) in formulation buffer. Care was takento ensure that each injection was made into the middle of the musclemass. In both groups, three mice were used for each time point. Micewere euthanized on days 1, 2, 3, 4, 7 and 14. The entire quadricepsmuscle was removed from each leg and muscles selected for RNA analysiswere snap frozen in liquid nitrogen and stored at −80 degrees Celsius.Total RNA was prepared for each sample. Equal amounts of RNA from thethree control samples were pooled to create a single control sample foreach time point.

[0347] GeneChip (Affymetrix, San Jose, Calif.) hybridization solutionswere prepared as described previously (Lockhart, D. J., et al. (1996)Nature Biotechnol. 14:1675-1680 and Wilson, S. B., et al. (2000) Proc.Nat. Acad Sci. USA 97:7411-7416). Murine Genome U74 chips (Affymetrixcat. # 900322, 900324, 900326) were scanned with the use of protocolsrecommended by Affymetrix and data was collected/reduced with the use ofthe GeneChip 3.1 application (Affymetrix). To identify differentiallyexpressed genes, GeneChip 3.1 was used to make three separate,time-matched, comparisons between a “pooled” buffer (control) and threehBMP-2 (experimental) samples.

[0348] Changes in gene expression, for each day of the experiment, werecompiled into an Excel table. This table contained only those genes thatsatisfied the following two criteria for at least one time point of theexperiment: i) the gene was Present in either or both the control andexperimental samples; and ii) relative to the control sample, geneexpression in the experimental sample was called Increasing orDecreasing. This composite table was imported into GeneSpring 3.2.12(Silicon Genetics) for graphical analysis and for the creation of theexpression profile gene lists. Table 1 lists genes on the U74 arraysthat show at least a two-fold increase in gene expression on at leastone day of the experiment. Table 2 lists genes on the U74 arrays thatshow at least a two-fold decrease in gene expression on at least one dayof the experiment.

[0349] An expression analysis using the RNA obtained as described abovewas also conducted on another gene microarray design called Mula (WyethResearch Division of Wyeth Pharmaceuticals, Inc.). Genes which werefound to be up- or down-regulated by a factor of at least about 4 areset forth in Tables 5 and 6. The numbers represent fold change (GeneFrequency_(BMP2)/Gene Frequency_(Buffer)) in gene expression+thestandard deviation (n=3). The genes listed in Table 6 and many otherslisted in Tables 1 and 2 do not appear to have been associated with boneor cartilage formation before.

Example 2 MMP23 and CLF-1 are Up-Regulated During Bone and CartilageFormation

[0350] Two genes which have not previously been known to be associatedwith bone or cartilage development appear to be up-regulated at veryhigh levels. The first gene is Cytokine Receptor-like Factor 1 (CLF-1)and the second gene is Matrix MetalloProtease 23 (MMP23). Graphsrepresenting the change in gene expression of each of these genes overtime during bone formation in the above-described animal model are setforth in FIGS. 1 and 2. These graphs show that CLF-1 is maximallyup-regulated about 15 fold and MMP23 is maximally upregulated about 40fold.

[0351] To identify cells that express MMP23 and CLF-1, in situhybridization was performed on tissue sections from mucles of miceinjected or not with recombinant hBMP-2. No signal was detected with asense or antisense probe directed against the message for CLF-1 in anycell type or at any time point in sections from muscles injected withbuffer only. In contrast, the anti-sense probe was detected in sectionsfrom muscle injected with hBMP-2. Staining was detected at all timepoints in this treatment group, and these results are summarized inTable 3. In particular, staining was observed in hypertrophicchondrocytes on day 7 and osteoblasts and some marrow cells on day 14.

[0352] No signal was detected with a sense or antisense probe directedagainst the message for MMP23 in any cell type or at any time point insections from muscles injected with buffer only. In contrast, theanti-sense probe detected MMP23 mRNA in sections from muscles injectedwith hBMP-2. Staining was detected at all time points in this treatmentgroup, and these results are summarized in Table 4. Staining wasobserved in hypertrophic chondrocytes and osteblasts on days 7 and 14,respectively. TABLE 3 Summary of cells stained with an antisense probefor CLF-1 mRNA* CLF-1 mRNA Day Treatment Positive Cell 1 2 3 4 7 14BUFFER Fibroblast Macrophage Chondrocyte- N/A N/A N/A N/A N/A N/A likeChondrocyte N/A N/A N/A N/A N/A N/A Marrow cell N/A N/A N/A N/A N/A N/AOsteoblast/ N/A N/A N/A N/A N/A N/A Osteocyte HBMP-2 Fibroblast + ++ ++++ − − Macrophage ++ + ++ ++ − − Chondrocyte- N/A N/A N/A ++ N/A N/Alike Chondrocyte N/A N/A N/A N/A + N/A Marrow cell N/A N/A N/A N/A N/A +Osteoblast/ N/A N/A N/A N/A N/A + Osteocyte

[0353] TABLE 4 Summary of cells stained with an antisense probe forMMP23 mRNA* MMP23 mRNA Day Treatment Positive Cell 1 2 3 4 7 14 BUFFERFibroblast Macrophage Chondrocyte- N/A N/A N/A N/A N/A N/A likeChondrocyte N/A N/A N/A N/A N/A N/A Marrow cell N/A N/A N/A N/A N/A N/AOsteoblast/ N/A N/A N/A N/A N/A N/A Osteocyte HBMP-2 Fibroblast + − − −− − Macrophage + − − − − − Chondrocyte- N/A N/A N/A + N/A N/A likeChondrocyte N/A N/A N/A N/A + N/A Marrow cell N/A N/A N/A N/A N/A −Osteoblast/ N/A N/A N/A N/A N/A + Osteocyte

[0354] Accordingly, the results show for the first time that CLF-1 andMMP23 are expressed in cells associated with bone and cartilage. Thesegenes will thus be useful targets in diagnostics and in drug design fordiseases relating to bone and cartilage formation.

Example 3 Patterns of Gene Expression During Particular Phases of BoneFormation

[0355] To identify genes with a particular expression profile, genes inTables 5 and 6 were analyzed with the use of GeneSpring, a data analysisprogram (Silicon Genetics, Redwood City, Calif.). GeneSpring identifiedgenes whose time-dependent expression profiles correlated with theprofiles of an exemplar gene. The correlation was based upon theprogram's standard correlation calculation, within the “Find Similar”function, and the confidence level was set to 95%. Four exemplar genes,cysteine rich protein 61 (Cyr61), procollagen type II alpha I (Col2a1),runt related transcription factor 2 (Runx2), and cathepsin K (Ctsk),were selected because their protein products appear to be phenotypicmarkers of one or more phases of endochondral bone formation. Cyr61 is amember of the CCN family of growth factors and is believed to regulatethe proliferation and differentiation of various connective tissue celltypes. Col2a1, Runx2 and Ctsk are well-defined markers for chondrocytes,osteoblasts and osteoclasts, respectively. The four lists (one for eachexemplar gene) of genes were compiled to create Table 7 and all geneswere segregated according to their membership in either Tables 5 or 6.

[0356] The temporal patterns of gene expression (Tables 5 and 6) suggestat least two possibilities. The first possibility for the observedtemporal patterns of gene expression is that there is some role for thegene products during the phase of bone formation in this model system.The second possibility is that patterns similar to the profiles of theexemplar genes in FIG. 3 may reveal some degree of gene co-regulation orfunctional connections between gene products. This comparative analysiscan be made qualitatively, by a visual inspection of the time-dependentexpression profiles in Tables 5 and 6, or quantitatively.Quantitatively, a data analysis program called GeneSpring identifiedgenes having expression profiles similar those of Cyr61, Col2a1, Runx2and Ctsk and these genes are listed in Table 7. Of the four exemplargenes, the correlation with Runx2 yielded the highest number of genes.It is interesting to note that several of the Runx2-like gene productsfrom Table 5 (Bmpl, Pcolce, Col5a1 and Bgn) have been functionallylinked in earlier studies of extracellular matrix proteins. For example,bone morphogenetic protein-1 (Bmp1), a member of the astacin family ofproteases, is also known as procollagen C-proteinase and is capable ofprocessing several forms of procollagen. Procollagen C-proteinaseenhancer (Pcolce) is an extracellular matrix glycoprotein that binds toprocollagen I and enhances the proteolytic activity of Bmp1 (which isalso capable of processing procollagen, type V alpha 1 (Col5a1) andprobiglycan (Bgn). Similarly, several Runx2-like gene products fromTable 6 (Pdgfrb, Fyn and Arhb) have been functionally linked.Platelet-derived growth factor receptor beta (pdgfrb) initiates asignaling cascade when activated by ligand. PDGF-BB, one of severalligands for Pdgfrb, has been shown to be an important growth factor formany cell types, including chondrocytes. Once activated by ligand,Pdgfrb has been shown to induce the phosphorylation and activation ofFyn, a member of the Src family of protein tyrosine kinases, in porcineaortic endothelial cells. In addition, Rat-2 fibroblasts exposed to PDGFshowed an increase in rhoB (Arhb; a member of the ras gene superfamilywhose products are GTP binding proteins) gene expression.

[0357] Equivalents

[0358] Those skilled in the art will recognize, or be able to ascertainusing no more than routine experimentation, many equivalents of thespecific embodiments of the invention described herein. Such equivalentsare intended to be encompassed by the following claims. TABLE 1Treatment Time BMP2 BMP2 BMP2 BMP2 BMP2 BMP2 day 01 day 02 day 03 day 04day 07 day14 Affymetrix Avg. Fold Avg. Fold Avg. Fold Avg. Fold Avg.Fold Avg. Fold Genbank Qualifier Change Change Change Change ChangeChange Gene Name Accession # 110451_at 2.76 4.33 4.35 2.49 0.00 3.90UNK_AI646968 AI646968 92315_at 2.86 0.00 6.24 8.35 0.00 3.87 SLFN4AF099977 93285_at 0.00 2.14 2.31 2.81 0.00 2.94 UNK_AI845584 AI845584103563_at 0.00 4.54 5.11 2.68 0.00 5.42 UNK_AW125713 AW125713 107566_at0.00 1.55 3.55 3.44 2.08 17.15 UNK_AI849532 AI849532 115395_at 0.00 2.233.68 2.97 0.00 2.37 UNK_AW208422 AW208422 92718_at 0.00 1.68 2.17 3.310.00 2.34 UNK_AI158810 AI158810 93975_at 0.00 1.77 2.83 3.21 0.00 3.8133 POLYPEPTIDE AI853531 [R. NORVEGICUS] 96752_at 1.65 2.58 0.00 3.130.00 2.46 ICAM1 M90551 103446_at 0.00 0.00 3.81 5.48 0.00 3.13UNK_AA959954 AA959954 104177_at 0.00 0.00 3.59 2.98 0.00 2.50UNK_AA204579 AA204579 104252_at 0.00 0.00 2.17 2.34 0.00 2.47UNK_AW123823 AW123823 108877_at 0.00 0.00 2.69 2.18 0.00 2.40UNK_AI790579 AI790579 109102_r_at 0.00 1.67 2.79 2.38 0.00 2.61UNK_AI838972 AI838972 109922_at 0.00 3.60 0.00 4.21 0.00 3.09UNK_AW122872 AW122872 112478_at 0.00 0.00 2.02 2.33 0.00 2.33UNK_AI853409 AI853409 112671_at 0.00 0.00 2.84 5.17 0.00 3.73UNK_AW122101 AW122101 113758_at 0.00 0.00 0.00 3.78 3.50 23.28UNK_AI843230 AI843230 115573_at 0.00 4.17 3.10 0.00 0.00 2.99UNK_AW047581 AW047581 130459_at 0.00 2.06 3.92 4.75 −1.78 0.00UNK_AI845691 AI845691 136655_f_at 0.00 0.00 2.87 3.14 0.00 2.39UNK_AI841502 AI841502 94354_at 0.00 0.00 0.00 2.22 0.00 3.75UNK_AI845514 AI845514 95303_at 1.49 2.01 0.00 0.00 0.00 2.63 0 AA14446996481_at 0.00 0.00 0.00 0.00 2.83 36.90 UNK_AV251613 AV251613 97448_at0.00 0.00 0.00 2.66 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0.00 0.00 0.00 0.00 0.00 2.64UNK_AA175228 AA175228 113316_at 0.00 0.00 0.00 0.00 0.00 3.21UNK_AI841062 AI841062 113319_at 0.00 0.00 0.00 0.00 0.00 3.04UNK_AI786159 AI786159 113339_at 0.00 0.00 0.00 0.00 0.00 2.24UNK_AW046072 AW046072 113554_at 0.00 0.00 0.00 0.00 0.00 2.53UNK_AI840943 AI840943 113579_at 0.00 0.00 0.00 0.00 0.00 2.33UNK_AI842229 AI842229 113680_at 0.00 0.00 0.00 1.91 0.00 2.52UNK_AI846297 AI846297 113737_at 0.00 0.00 0.00 0.00 0.00 2.30UNK_AW122351 AW122351 113790_at 0.00 0.00 0.00 1.63 0.00 3.67UNK_AI194566 AI194566 114005_at 0.00 0.00 0.00 1.75 0.00 3.24UNK_AW215403 AW215403 114016_at 0.00 0.00 0.00 0.00 0.00 2.30UNK_AW124568 AW124568 114045_at 0.00 0.00 0.00 0.00 0.00 2.70UNK_AI877454 AI877454 114149_at 0.00 0.00 0.00 0.00 0.00 2.05UNK_AA596704 AA596704 114197_at 0.00 0.00 0.00 0.00 0.00 4.89UNK_AI643902 AI643902 114213_at 0.00 0.00 0.00 0.00 0.00 2.45UNK_AA242681 AA242681 114270_at 0.00 0.00 0.00 0.00 0.00 12.52UNK_AW049906 AW049906 114281_at 0.00 0.00 0.00 1.98 0.00 5.21UNK_AI593204 AI593204 114309_at 0.00 0.00 0.00 0.00 0.00 2.11UNK_AA716898 AA716898 114390_at 0.00 0.00 0.00 0.00 0.00 4.05UNK_AI464339 AI464339 114408_at 0.00 0.00 0.00 0.00 0.00 2.77UNK_AI843543 AI843543 114463_at 0.00 0.00 0.00 0.00 0.00 2.40UNK_AI585881 AI585881 114485_at 0.00 0.00 0.00 1.71 0.00 2.72UNK_AI596717 AI596717 114619_at 0.00 0.00 0.00 1.83 0.00 2.26UNK_AA797871 AA797871 114686_at 0.00 0.00 0.00 0.00 0.00 2.30UNK_AW048693 AW048693 114716_at 0.00 0.00 0.00 0.00 0.00 2.26UNK_AI181770 AI181770 114752_at 0.00 −2.01 0.00 0.00 0.00 2.84UNK_AI843572 AI843572 114755_at 0.00 0.00 0.00 0.00 0.00 2.34UNK_AI844350 AI844350 114804_at 0.00 0.00 0.00 0.00 0.00 2.22 NNATAI154029 114836_at 0.00 0.00 0.00 0.00 0.00 4.17 UNK_AI536480 AI536480114854_at 0.00 0.00 0.00 0.00 0.00 5.39 UNK_AI843070 AI843070 114917_at0.00 0.00 0.00 0.00 0.00 4.31 UNK_AI118679 AI118679 114980_at 0.00 0.000.00 0.00 0.00 2.28 UNK_AI854024 AI854024 115004_at 0.00 0.00 0.00 0.000.00 2.23 UNK_AI788664 AI788664 115017_at 0.00 0.00 0.00 1.79 0.00 2.11UNK_AI848298 AI848298 115058_at 0.00 0.00 0.00 0.00 0.00 3.62UNK_AA756546 AA756546 115110_at 0.00 0.00 0.00 0.00 0.00 2.93UNK_AA250358 AA250358 115114_at 0.00 0.00 0.00 0.00 0.00 3.74UNK_AW047112 AW047112 115202_at 0.00 0.00 0.00 0.00 0.00 5.05UNK_AI851969 AI851969 115398_at 0.00 0.00 0.00 0.00 0.00 2.07UNK_AA990038 AA990038 115612_at 0.00 0.00 0.00 0.00 0.00 9.42UNK_AA175284 AA175284 115664_at 0.00 0.00 0.00 0.00 0.00 2.15UNK_AA222756 AA222756 115679_at 0.00 0.00 0.00 0.00 0.00 2.09UNK_AA174839 AA174839 115692_r_at 0.00 0.00 0.00 0.00 0.00 2.88UNK_AA396015 AA396015 115741_at 0.00 0.00 0.00 0.00 0.00 2.52UNK_AW125843 AW125843 116096_at 0.00 0.00 0.00 0.00 0.00 2.33UNK_AA718043 AA718043 116113_at 0.00 0.00 0.00 0.00 0.00 4.05UNK_AI790538 AI790539 116149_at 0.00 0.00 0.00 0.00 0.00 4.15UNK_AI155421 AI155421 116337_at 0.00 0.00 0.00 0.00 0.00 3.22UNK_AI390374 AI390374 116346_at 0.00 0.00 0.00 0.00 0.00 6.82UNK_AI843913 AI843913 116380_at 0.00 0.00 0.00 0.00 0.00 2.70UNK_AI227104 AI227104 116408_at 0.00 0.00 0.00 0.00 0.00 3.16UNK_AI851073 AI851073 116488_f_at 0.00 0.00 0.00 0.00 0.00 5.95UNK_AA178300 AA178300 116489_r_at 0.00 0.00 0.00 0.00 0.00 2.99UNK_AA178300 AA178300 116526_at 0.00 0.00 0.00 0.00 0.00 8.92UNK_AW121457 AW121457 116629_at 0.00 0.00 0.00 0.00 0.00 6.07UNK_AW215503 AW215503 116642_f_at 0.00 0.00 0.00 0.00 0.00 5.54UNK_AI852563 AI852563 116672_at 0.00 0.00 0.00 0.00 0.00 3.31UNK_AA611861 AA611861 116755_at 0.00 0.00 0.00 0.00 0.00 2.12UNK_AI835947 AI835947 116786_at 0.00 0.00 0.00 0.00 0.00 9.07UNK_AI850351 AI850351 116936_f_at 0.00 0.00 0.00 0.00 0.00 2.55UNK_AI847709 AI847709 117043_at 0.00 0.00 0.00 0.00 0.00 2.19UNK_AI851915 AI851915 117056_at 0.00 0.00 0.00 0.00 0.00 2.24UNK_AI837103 AI837103 117120_at 0.00 0.00 0.00 0.00 0.00 3.42UNK_AW124145 AW124145 117263_at 0.00 0.00 0.00 0.00 0.00 2.90UNK_AI850544 AI850544 117297_at 0.00 0.00 0.00 0.00 0.00 2.56UNK_AI846211 AI846211 117302_at 0.00 0.00 0.00 0.00 0.00 2.95UNK_AI847477 AI847477 128837_f_at 0.00 0.00 0.00 0.00 0.00 4.79UNK_AA726602 AA726602 129125_at 0.00 0.00 0.00 0.00 0.00 5.05UNK_AA475062 AA475062 129284_at 0.00 0.00 0.00 0.00 0.00 3.32UNK_AA154872 AA154872 129320_at 0.00 0.00 0.00 0.00 0.00 3.25UNK_AI593773 AI593773 130499_at 0.00 −1.75 0.00 0.00 0.00 2.16UNK_AW108404 AW108404 132374_at 0.00 0.00 0.00 0.00 0.00 2.21UNK_AI467276 AI467276 133489_f_at 0.00 0.00 0.00 1.65 0.00 2.50UNK_AI449387 AI449387 133743_at 0.00 0.00 0.00 0.00 0.00 3.92UNK_AI467607 AI467607 133851_s_at 0.00 0.00 0.00 1.80 0.00 2.39UNK_AU019736 AU019736 134141_at 0.00 0.00 0.00 0.00 0.00 3.08UNK_AA189644 AA189644 135248_at 0.00 0.00 0.00 0.00 0.00 3.48UNK_AI843905 AI843905 135716_f_at 0.00 0.00 0.00 0.00 0.00 37.37UNK_AI836970 AI836970 136580_at 0.00 1.40 0.00 2.03 0.00 1.59UNK_AI428854 AI428854 136798_at 0.00 0.00 0.00 0.00 0.00 2.31UNK_AI536255 AI536255 137203_f_at 0.00 0.00 0.00 0.00 0.00 5.09UNK_AI661008 AI661008 137569_at 0.00 0.00 0.00 0.00 0.00 2.28UNK_AI605650 AI605650 139200_at 0.00 0.00 0.00 0.00 0.00 2.05UNK_AW045408 AW045408 140629_s_at 0.00 0.00 0.00 1.28 0.00 2.38UNK_AI506220 AI506220 140759_at 0.00 0.00 0.00 0.00 0.00 5.94UNK_AI646554 AI646554 140820_at 0.00 0.00 0.00 0.00 0.00 2.91UNK_AI662586 AI662586 140840_at 0.00 0.00 0.00 0.00 0.00 2.96UNK_AI791094 AI791094 94079_at 0.00 0.00 0.00 0.00 0.00 2.57 homologX61452 (Drosophila); Pnutl2 110428_at 0.00 0.00 0.00 1.81 0.00 2.31UNK_AA797538 AA797538 112746_at 0.00 0.00 0.00 0.00 0.00 2.54UNK_AW260381 AW260381 102873_at 0.00 0.00 0.00 1.90 0.00 2.96 TAP2U60091 98859_at 0.00 0.00 0.00 7.40 5.86 101.96 tartrate resistant;M99054 Acp5 99104_at 0.00 −0.86 0.00 0.00 0.00 2.83 ACRP30 U4991598589_at 0.00 1.38 0.00 2.93 0.00 2.22 differentiation M93275 relatedprotein; Adfp 99559_at 0.00 0.00 0.00 0.00 0.00 2.62 dehydrogenaseU14390 family 3, subfamily A2; Aldh3a2 93354_at 0.00 0.00 0.00 0.00 0.003.14 Apoc1 Z22661 104155_f_at 0.00 0.00 0.00 0.00 0.00 2.14transcription factor U19118 3; Atf3 95744_at 0.00 0.00 0.00 0.00 0.006.19 ATPase, H+ U13837 transporting, lysosomal (vacuolar proton pump),alpha 70 kDa, isoform 2; 92597_s_at 0.00 0.00 0.00 0.00 0.00 7.95ATPase, H+ U13838 transporting, lysosomal (vacuolar proton pump), beta56/58 kDa, isoform 2; 92598_at 0.00 0.00 0.00 0.00 0.00 5.12 ATP6B2AI843029 94532_at 0.00 0.00 0.00 0.00 0.00 2.12 transporting U13841lysosomal (vacuolar proton pump), 32 kDa; Atp6e 103205_at 0.00 0.00 0.007.48 7.29 36.60 ATP6I AI286861 130186_f_at 0.00 0.00 0.00 0.00 0.00 2.13ATP6I AW211999 96919_at 0.00 0.00 0.00 0.00 0.00 2.22 vacuolar protonM64298 channel; Atpl 94043_at 0.00 0.00 0.00 0.00 0.00 2.47 ATP6S1AB031290 112716_at 0.00 0.00 0.00 0.00 0.00 2.06 UNK_AW122682 AW12268294189_at 0.00 0.00 0.00 0.00 0.00 2.17 BAZF AB011665 100336_s_at 0.000.00 0.00 0.00 7.91 53.48 BGLAP1 L24431 93605_r_at −1.20 0.00 0.00 0.000.00 4.12 BL2 AF061260 92982_at 0.00 0.00 0.00 0.00 0.00 2.65 bonemorphogenetic M97017 protein 8a; Bmp8a 96255_at 0.00 0.00 0.00 0.00 0.002.02 BNIP3L AF067395 92668_at 0.00 2.99 1.99 1.78 0.00 3.12agammaglobulinemia L10627 tyrosine kinase; Btk 106304_at 0.00 0.00 0.000.00 0.00 2.83 C1S AW215831 112110_at 0.00 0.00 0.00 0.00 0.00 2.07CAMKK AI843712 92642_at 0.00 0.00 −2.16 0.00 −2.62 5.27 CAR2 M25944102905_at 0.00 1.80 0.00 2.52 0.00 1.94 CASP11 Y13089 98437_at 0.00 0.000.00 0.00 0.00 7.81 CASP3 U63720 98498_at 0.00 0.00 0.00 1.75 0.00 2.28CASP7 D86353 97832_at 0.00 0.00 0.00 0.00 0.00 2.22 CD97 AA75488798447_at 0.00 1.36 1.37 1.74 0.00 2.25 binding protein M62362 (C/EBP),alpha; Cebpa 114787_at 0.00 0.00 0.00 0.00 0.00 2.46 UNK_AW107224AW107224 102027_s_at 0.00 0.00 0.00 0.00 0.00 2.16 CHETK AA20401092694_at 2.21 2.77 2.17 0.00 0.00 3.52 Chi3I3 M94584 99070_at 0.00 0.001.95 2.74 0.00 2.05 conserved helix-loop- U12473 helix ubiquitouskinase; Chuk 137242_f_at 0.00 0.00 0.00 0.00 0.00 27.84 CKB AI83668993595_at 0.00 0.00 0.00 0.00 0.00 2.11 CLN2 AF111172 99413_at 2.76 5.612.96 3.04 2.59 16.03 CMKBR1 U29678 134879_at 0.00 0.00 0.00 0.00 0.002.62 COL11A2 AI324726 98782_at 0.00 0.00 0.00 0.00 0.00 2.10 complexin2; Cplx2 D38613 93198_at 0.00 0.00 0.00 0.00 0.00 3.45 colonystimulating M58288 factor 3 receptor (granulocyte); Csf3r 95608_at 0.001.92 2.08 3.00 0.00 2.77 CTSB AI851255 104696_at 0.00 0.00 0.00 0.000.00 2.99 CTSE AJ009840 97336_at 0.00 −2.65 0.00 0.00 0.00 2.12UNK_AJ131851 AJ131851 100069_at 0.00 0.00 0.00 0.00 0.00 3.27 cytochromeP450, M77497 2f2; Cyp2f2 97526_at 0.00 0.00 0.00 0.00 0.00 2.67 LOC55946AW123294 101960_at 0.00 0.00 0.00 2.59 0.00 1.98 D10WSU52E AI842208114696_at 0.00 0.00 0.00 0.00 0.00 2.72 UNK_AW046335 AW046335 112306_at0.00 0.00 0.00 0.00 0.00 2.37 UNK_AW121212 AW121212 92610_at 0.00 0.000.00 2.19 0.00 2.64 DNA segment, Chr M21332 17, human D6S45; D17H6S45104391_s_at 0.00 0.00 0.00 0.00 0.00 2.95 D17WSU51E AI850563 115816_at0.00 0.00 0.00 0.00 0.00 5.54 UNK_AA869817 AA869817 103877_at 0.00 0.000.00 0.00 0.00 2.28 D2WSU58E AW060485 99143_at 0.00 0.00 0.00 0.00 0.002.35 TTGN1 AA614914 113046_at 0.00 0.00 0.00 0.00 0.00 2.45 TTGN1AI842091 96561_at 0.00 0.00 0.00 0.00 0.00 2.30 UNK_AI157475 AI157475108293_at 0.00 0.00 0.00 0.00 0.00 4.29 UNK_AI592230 AI592230 97863_at0.00 0.00 0.00 0.00 0.00 2.09 UNK_AW125274 AW125274 110406_at 0.00 0.000.00 0.00 0.00 2.63 UNK_AA958839 AA958839 99506_at 0.00 0.00 0.00 0.000.00 2.25 DAPK2 AB018002 99025_at 0.00 0.00 0.00 0.00 0.00 3.32Ala-Asp/His) box L25125 polypeptide 19; Ddx19 104371_at 0.00 0.00 0.000.00 0.00 2.06 DGAT AF078752 99881_at 0.00 0.00 0.00 0.00 0.00 3.49 DKK1AF030433 99328_at 0.00 0.00 0.00 0.00 0.00 3.37 distal-less U79738homeobox 3; Dlx3 99903_at 0.00 0.00 0.00 0.00 9.98 51.29 DMP1 AJ242625114809_at 0.00 0.00 0.00 0.00 0.00 3.58 DOKL-PENDING AW046136 94052_at0.00 0.00 0.00 0.00 0.00 2.34 DPM2 AB013360 92535_at 0.00 0.00 0.00 0.000.00 3.27 Ebf L12147 104492_at 0.00 0.00 0.00 0.00 0.00 2.18 earlyB-cell factor 3; U92702 Ebf3 102996_at 0.00 0.00 0.00 0.00 0.00 2.11lysine-rich leukemia U80227 gene; Ell 92207_at 0.00 0.00 0.00 0.00 0.003.03 elastin; Eln U08210 107900_at 0.00 0.00 0.00 2.56 0.00 2.12UNK_AW123554 AW123554 102771_at 0.00 0.00 0.00 0.00 0.00 2.62 ESETAF091628 107996_at 0.00 0.00 0.00 0.00 0.00 2.27 ESTM573010 AW04905092267_at 0.00 0.00 0.00 0.00 0.00 5.46 F2R L03529 94307_at 0.00 0.000.00 0.00 0.00 3.38 fibulin 1; Fbln1 X70854 100928_at −4.16 0.00 0.002.21 −0.01 19.58 fibulin 2; Fbln2 X75285 102366_at 0.00 0.00 −5.06 −3.750.00 2.31 UNK_AA718169 AA718169 95295_s_at 0.00 0.00 0.00 0.00 0.00 2.74FMS-like tyrosine X59398 kinase 3; Flt3 101422_at 0.00 0.00 0.00 0.000.00 2.07 FNBP4 AW121377 92959_at 0.00 0.00 0.00 0.00 0.00 2.21 B-cellsrc-homology Z48757 tyrosine kinase; Frk 102016_at 0.00 −1.46 0.00 0.000.00 3.68 fat specific gene 27; M61737 Fsp27 94966_at 0.00 1.70 0.001.97 0.00 2.99 phosphate Z11911 dehydrogenase X- linked; G6pdx 100407_at0.00 0.00 0.00 0.00 0.00 2.99 galanin; Gal L38580 96998_at 0.00 0.000.00 0.00 0.00 7.44 UNK_AJ133523 AJ133523 94813_at 0.00 0.00 0.00 0.000.00 2.85 growth arrest X65128 specific 1; Gas1 104597_at 0.00 0.00 3.302.90 0.00 6.62 GBP2 AJ007970 104134_at 0.00 0.00 0.00 0.00 0.00 2.51GDAP2 Y17851 92534_at 0.00 0.00 0.00 0.00 0.00 2.86 (gene U10551overexpressed in skeletal muscle); 102968_at 0.00 0.00 0.00 0.00 0.003.69 GGTLA1 AF077765 97384_at 0.00 2.67 3.42 0.00 0.00 2.09 UNK_AA791012AA791012 100514_at 0.00 0.00 0.00 0.00 0.00 2.43 guanine nudeotideM63660 binding protein, alpha 13; Gna13 93080_at 0.00 0.00 0.00 0.000.00 3.13 GNG3LG AF069954 97385_at 0.00 0.00 0.00 0.00 0.00 2.76GNK-PENDING AJ242909 100565_at 0.00 1.93 2.25 2.33 0.00 2.45 GNPIAW123396 96553_at 0.00 2.13 3.60 0.00 0.00 1.56 G-protein coupled U39827receptor 25; Gpcr25 100594_at 0.00 0.00 0.00 2.29 0.00 2.00glycosylphosphatidyl AB008895 inositol 1 homolog (human); Gpi1h104256_at 1.79 1.75 0.00 0.00 0.00 2.53 UNK_AI120844 AI120844102995_s_at 0.00 0.00 0.00 0.00 0.00 2.21 GZMA M13226 93092_at 0.00 1.490.00 0.00 0.00 4.62 histocompatibility 2, U35323 class II, locus Dma,histocompatibility 2, class II, locus Mb1, histocompatibility 2, classII, locus Mb2, proteosome (prosome, macropain) subunit, beta type 9(large multifunctional protease 2); H2- DMa, H2-DMb1, H2- 93120_f_at0.00 0.00 0.00 2.02 0.00 2.69 H2-K V00746 101876_s_at 0.00 0.00 1.962.42 0.00 2.64 UNK_M35247 M35247 98284_f_at 0.00 0.00 0.00 0.00 0.005.93 H2-T18 X03052 101523_at 0.00 0.00 0.00 2.34 0.00 1.86 H3F3AAW046194 111423_at 0.00 0.00 0.00 0.00 0.00 3.30 UNK_AI852812 AI852812100966_at 0.00 0.00 0.00 0.00 0.00 3.32 Hcf2 U07425 104194_at 0.00 0.000.00 0.00 0.00 2.51 HEPH AF082567 104502_f_at 0.00 0.00 0.00 0.00 0.004.35 HES6 AI414025 107620_at 0.00 0.00 0.00 0.00 0.00 2.16 HIPK1AW125573 98038_at 0.00 0.00 0.00 2.31 0.00 3.06 HMG4 AF022465 93378_at0.00 0.00 0.00 0.00 0.00 3.93 Hoxc8 X07439 103835_f_at 0.00 0.00 0.000.00 0.00 3.00 HPCAL1 AF085192 98962_at 0.00 0.00 0.00 0.00 0.00 4.30hepatic lipase; Hpl X58426 96144_at 0.00 0.00 0.00 0.00 0.00 2.40 IDB4AJ001972 104500_at 0.00 0.00 0.00 0.00 0.00 2.01 Idua L34111 92773_at0.00 0.00 0.00 1.95 0.00 2.30 IER5 AF079528 97409_at 0.00 0.00 2.03 3.550.00 2.64 interferon inducible U19119 protein 1; Ifi1 93321_at 0.00 0.000.00 2.88 0.00 2.59 interferon activated AF022371 gene 203; Ifi203103963_f_at 0.00 0.00 6.13 0.00 0.00 12.91 UNK_AA914345 AA914345137251_f_at 0.00 0.00 0.00 0.00 0.00 3.68 UNK_AI449282 AI44928294398_s_at 0.00 0.00 0.00 0.00 0.00 2.79 INPP5B AF040094 99034_at 0.000.00 0.00 0.00 0.00 2.23 IRX3 Y15001 98828_at 1.64 3.70 0.00 1.93 0.001.84 integrin alpha M X07640 (Cd11b); Itgam 99904_at 0.00 0.00 0.00 0.000.00 2.18 ITGB3 AF026509 1700906_at 0.00 0.00 0.00 0.00 0.00 4.05 ITGB7M68903 99577_at 0.00 0.00 0.00 0.00 0.00 2.21 KITL M57647 97761_f_at0.00 0.00 0.00 0.00 0.00 2.29 killer cell lectin-like U10094 receptor,subfamily A, member 7; Klra7 97762_f_at 0.00 0.00 0.00 0.00 0.00 2.56KLRA7 U12890 99993_at 0.00 0.00 0.00 0.00 0.00 2.25 leucine U77083arylaminopeptidase 1, intestinal; Lap1 104658_at 0.00 0.00 0.00 0.001.22 12.86 LIFR D17444 96810_at 0.00 0.00 0.00 0.00 0.00 2.15 LMO2AI154017 97980_at 0.00 0.00 0.00 0.00 0.00 2.54 LTBR L38423 92401_at0.00 0.00 0.00 0.00 0.00 2.01 leukotriene C4 U27195 synthase; Ltc4s96089_at 0.00 0.00 0.00 0.00 0.00 2.20 UNK_AI255972 AI255972 93454_at0.00 1.58 0.00 2.37 0.00 2.17 LY68 AF081789 92216_at 4.83 3.87 2.49 0.000.00 1.72 MADH7 AF015260 103020_s_at 0.00 0.00 0.00 0.00 0.00 2.15MAP3K1 AI317205 101834_at 0.00 0.00 0.00 2.51 0.00 3.21 protein kinase3; Z14249 Mapk3 96003_at 0.00 0.00 0.00 0.00 0.00 2.67 MATA1L1 AW04833296310_at 0.00 0.00 0.00 0.00 0.00 2.98 MBP L07508 101070_at 0.00 0.000.00 0.00 0.00 2.92 MKRN1 AW125438 100484_at 0.00 0.00 0.00 1.38 21.43135.83 metalloproteinase X66473 13; Mmp13 100414_s_at 0.00 0.00 −1.840.00 0.00 2.69 MPO X15313 97719_at 0.00 0.00 0.00 0.00 0.00 9.46 ROWX74736 95340_at 0.00 0.00 0.00 0.00 0.00 3.06 Mt3 M93310 102096_f_at0.00 0.00 −2.42 0.00 0.00 3.13 MUP1 AI255271 101909_f_at 0.00 0.00 −4.140.00 0.00 3.70 MUP3 M16357 101910_f_at 0.00 0.00 0.00 0.00 0.00 3.19major urinary protein M16359 3; Mup3 101682_f_at 0.00 0.00 0.00 0.000.00 3.68 major urinary protein M16358 4; Mup4 94122_at 7.47 3.44 2.580.00 −3.81 −1.94 MYOC AF041335 103662_at 2.05 2.83 5.66 5.71 0.00 5.18neutrophil cytosolic U59488 factor 4; Ncf4 97843_at 0.00 0.00 0.00 0.000.00 2.39 UNK_AI834866 AI834866 101554_at 0.00 0.00 0.00 9.53 0.00 3.44NFKBIA U57524 104149_at 0.00 0.00 0.00 1.87 0.00 2.95 NFKBIA AI642048100120_at 0.00 0.00 0.00 0.00 0.00 2.41 NID1 L17324 94982_f_at 0.00 0.000.00 0.00 0.00 2.13 UNK_AI852470 AI852470 97497_at 0.00 0.00 0.00 0.000.00 3.34 1, (Drosophila); Z11886 Notch 1 95016_at 0.00 1.82 1.85 2.130.00 2.03 neuropilin; Nrp D50086 100436_at 0.00 0.00 0.00 0.00 0.00 2.35Orm1 M27008 103029_at 0.00 0.00 0.00 0.00 0.00 2.74 programmed cellD86344 death 4; Pdcd4 95040_at 0.00 0.00 0.00 0.00 0.00 2.02UNK_AI840810 AI840810 95079_at 0.00 0.00 0.00 0.00 0.00 3.53 PDGFRAM57683 93039_at 0.00 0.00 0.00 0.00 0.00 2.50 HLS2 AF009513 96502_at0.00 0.00 0.00 0.00 0.00 2.85 regulating neutral U75646 endopeptidaseson the X chromosome; Phex 130145_i_at 0.00 0.00 0.00 0.00 1.36 25.36PHEX AI481510 130146_f_at 0.00 0.00 0.00 0.00 1.68 14.49 PHEX AI481510103573_at 0.00 0.00 0.00 0.00 0.00 3.43 4-phosphate 5- D86176 kinase,type 1 alpha; Pip5k1a 101865_at 0.00 0.00 0.00 0.00 0.00 4.51 PIP5K2AAB009615 99510_at 0.00 0.00 0.00 0.00 0.00 4.15 PKCB X59274 99916_at0.00 0.00 0.00 0.00 0.00 3.44 protein kinase C, D90242 eta; Pkch100707_at 0.00 0.00 0.00 0.00 0.00 2.05 UNK_AF030131 AF030131 97926_s_at0.00 0.00 2.13 0.00 0.00 2.82 PPARG U10374 113154_at 0.43 0.00 −2.71−1.11 −2.08 2.44 UNK_AI854500 AI854500 92904_at 0.00 0.00 0.00 0.00 0.003.09 containing 1, with U08185 ZNF domain; Prdm1 110362_at 0.00 0.000.00 0.00 0.00 2.90 UNK_AW046410 AW046410 94085_at 0.00 0.00 0.00 0.000.00 2.37 PRG M34603 96957_at 0.00 0.00 0.00 0.00 0.00 3.05 PENDINGAB006463 94454_at 0.00 0.00 0.00 2.36 0.00 1.70 PRTB AF085348 101486_at0.00 0.00 0.00 0.00 0.00 2.88 PSMB10 Y10875 93085_at 0.00 3.16 6.20 5.370.00 6.03 PSMB9 D44456 112345_at 0.00 0.00 0.00 0.00 0.00 2.81UNK_AI841610 AI841610 92356_at 0.00 0.00 0.00 0.00 0.00 5.19phosphatase, non- M90388 receptor type 8; Ptpn8 101932_at 0.00 0.00 0.002.02 0.00 3.46 PTPRE D83484 92309_i_at 0.00 0.00 0.00 0.00 0.00 2.50phosphatase, X58287 receptor-type, M; Ptprm 92854_at 0.00 1.77 0.00 2.370.00 1.82 RAS oncogene D50500 family; Rab11a 100459_at 0.00 0.00 0.000.00 0.00 2.57 RAD50 homolog (S. U66887 cerevisiae); Rad50 99032_at 0.000.00 0.00 0.00 0.00 2.73 dexamethasone- AF009246 induced 1; Rasd1104618_at 0.00 0.00 0.00 0.00 0.00 2.22 RBBP9 AI845819 97848_at 0.000.00 0.00 0.00 0.00 2.19 RBMX AJ237846 100530_at 0.00 0.00 0.00 0.000.00 2.57 nucleotide L07924 dissociation stimulator; Rgds 97844_at 0.000.00 2.15 2.25 0.00 3.16 protein signaling 2; U67187 Rgs2 102762_r_at0.00 0.00 0.00 0.00 0.00 2.08 RHAG AF057527 100980_at 0.00 0.00 0.000.00 0.00 2.13 Rho-associated U58512 coiled-coil forming kinase 1; Rock193839_at 0.00 0.00 0.00 0.00 0.00 2.28 RTN3 AI854888 102336_at 0.00 0.000.00 0.00 0.00 2.06 RW1 AF060565 103448_at 0.00 2.51 −4.75 −1.37 −6.473.81 binding protein A8 M83218 (calgranulin A); S100a8 103887_at 4.410.00 −8.99 −5.52 −6.50 5.43 binding protein A9 M83219 (calgranulin B);S100a9 103715_at 0.00 0.00 0.00 0.00 0.00 3.21 scinderin; Scin U04354101436_at 0.00 0.00 3.77 3.82 0.00 6.09 cytokine B subfamily M34815(Cys-X-Cys), member 9; Scyb9 100112_at 0.00 0.00 0.00 0.00 0.00 5.61derived factor 1; L12030 Sdf1 103488_at 0.00 1.89 2.03 2.49 0.00 6.53selectin) ligand; X91144 Selpl 92469_at 0.00 0.00 0.00 0.00 0.00 6.76SFRP4 AF117709 96126_at 0.00 0.00 0.00 0.00 0.00 4.16 SGPL1 AF03689496682_at 0.00 0.00 0.00 0.00 0.00 3.69 SIAT7D Y15780 102318_at 0.00 0.000.00 0.00 0.00 3.68 sialyltransferase 8 X86000 (alpha-2, 8-sialytransferase) D; Siat8d 110381_at 0.00 0.00 0.00 1.54 0.00 2.32 SLAPAI120030 92582_at 0.00 0.00 0.00 0.00 0.00 2.81 solute carrier familyL42115 1, member 7; Slc1a7 103347_at 0.00 0.00 0.00 0.00 0.00 2.45UNK_AI852548 AI852548 109069_at 0.00 −2.82 −2.00 0.00 0.00 3.28 SLC39A1AI255982 98299_s_at 2.97 0.00 0.00 2.13 0.00 1.52 SLFN3 AF099974115731_at 0.00 0.00 0.00 0.00 0.00 2.37 UNK_AA896535 AA896535100422_i_at 0.00 0.00 0.00 0.00 0.00 2.96 STAT5A AJ237939 93680_at 0.000.00 0.00 0.00 0.00 2.99 STK10 D89728 100425_at 0.00 1.48 0.00 0.00 0.003.69 SYK U25685 95066_at 0.00 0.00 0.00 0.00 0.00 2.20 Taldo1 U67611103328_at 0.00 0.00 0.00 2.54 0.00 2.23 TANK U59864 98087_at 0.00 0.000.00 1.88 0.00 2.80 UNK_AW048562 AW048562 92387_at 0.00 0.00 0.00 0.000.00 2.03 synthase 1, platelet; L18868 Tbxas1 1703539_at 0.00 0.00 0.000.00 0.00 4.07 cytoplasmic X55663 tyrosine kinase, Dscr28C related(Drosophila); Tec 92427_at 0.00 0.00 0.00 0.00 0.00 2.71 transforminggrowth D25540 factor, beta receptor I; Tgfbr1 102637_at 0.00 0.00 0.000.00 0.00 6.10 TGFBR3 AF039601 113920_at −1.60 0.00 0.00 0.00 0.00 2.12UNK_AI021069 AI021069 102906_at 0.00 0.00 2.95 3.25 0.00 9.29 T-cellspecific L38444 GTPase; Tgtp 99602_at 0.00 1.29 0.00 2.02 0.00 1.67 TIEGAF064088 101964_at 0.00 0.00 −2.16 0.00 0.00 3.47 transketolase; TktU05809 97893_at 0.00 0.00 0.00 0.00 0.00 2.01 TLP AB017697 111478_at0.00 0.00 0.00 1.96 0.00 2.34 UNK_AI047601 AI047601 96700_r_at 0.00 0.000.00 0.00 0.00 2.46 UBL1A2-PENDING AW060594 99580_s_at 0.00 1.50 0.001.61 0.00 2.44 UGT1A1 U16818 92760_at 0.00 5.57 3.44 0.00 0.00 4.76 WASPU42471 94704_at 2.27 0.00 0.00 0.00 0.00 9.98 WISP2 AF100778 97950_at0.00 0.00 0.00 2.32 0.00 2.77 xanthine X75129 dehydrogenase; Xdh98053_at 0.00 1.87 0.00 2.77 0.00 2.11 YWHAB AF058797 97060_at 0.00 0.000.00 0.00 0.00 2.95 YWHAQ AW215489 93013_at 3.57 3.97 3.52 5.65 7.056.32 IDB2 AF077861 96331_at 2.04 2.99 2.67 3.12 2.54 2.59 UNK_AI842754AI842754 99051_at 2.16 3.59 4.32 7.61 3.35 4.76 S100A4 M36579102104_f_at 2.36 3.77 6.03 8.42 3.97 5.52 UNK_AI504305 AI504305109403_at 2.15 3.73 5.34 10.02 4.37 19.28 UNK_AW121933 AW121933114810_at 2.97 9.08 11.55 9.62 8.54 4.12 UNK_AI447446 AI447446 130509_at2.64 4.77 7.87 6.94 2.24 2.18 UNK_AI851996 AI851996 92810_at 0.00 3.054.26 5.46 10.73 9.24 UNK_AI842259 AI842259 92850_at 0.00 2.42 2.43 6.719.75 6.66 UNK_AI836446 AI836446 93548_at 0.00 2.61 2.07 3.67 4.32 2.86UNK_AW122942 AW122942 93829_at 0.00 2.05 3.42 3.58 3.28 5.01UNK_AW107884 AW107884 93842_at 0.00 2.97 3.69 7.34 12.44 11.01UNK_AI196645 AI196645 94792_at 3.10 5.07 4.52 4.71 2.76 0.00UNK_AI447305 AI447305 95102_at 0.00 2.19 2.59 3.61 3.09 3.88UNK_AW123754 AW123754 95152_g_at 0.00 3.22 2.73 3.00 4.27 4.52UNK_AW061307 AW061307 95417_at 0.00 2.59 3.27 3.18 3.80 3.54UNK_AI117848 AI117848 95466_at 0.00 5.84 6.73 4.76 5.82 4.94UNK_AI837006 AI837006 95542_at 0.00 2.62 2.69 4.54 5.75 4.80UNK_AI835858 AI835858 95543_at 0.00 3.08 3.87 4.77 4.36 4.23UNK_AI843046 AI843046 95647_f_at 0.00 2.65 2.69 3.32 3.84 4.28UNK_AI465845 AI465845 95654_at 0.00 3.23 3.45 5.80 4.72 5.58UNK_AF109905 AF109905 95673_s_at 0.00 2.31 2.83 5.79 6.60 5.31UNK_AW124113 AW124113 95749_at 0.00 2.30 2.14 5.13 4.36 3.10UNK_AW122364 AW122364 95940_f_at 1.92 3.66 5.69 6.58 4.38 7.39UNK_AW047237 AW047237 96135_at 0.00 2.38 3.85 7.06 6.16 10.09UNK_AA833425 AA833425 96168_at 0.00 3.47 4.05 3.80 5.45 3.82UNK_AI591702 AI591702 96319_at 0.00 5.82 5.05 13.49 5.11 6.19UNK_AW061324 AW061324 96333_g_at 0.00 2.97 2.46 3.17 2.53 2.19UNK_AW259199 AW259199 96784_at 0.00 4.17 5.63 6.89 5.90 3.14UNK_AW123269 AW123269 96811_at 1.20 4.20 5.77 6.75 9.85 12.17UNK_AW049806 AW049806 96834_at 0.00 2.06 2.03 3.08 3.82 4.91UNK_AI843586 AI843586 96885_at 0.00 5.55 6.66 17.42 21.15 8.95UNK_AW122271 AW122271 96886_at 0.00 3.53 3.88 3.89 3.05 3.28UNK_AW060556 AW060556 97444_at 0.00 4.08 4.33 11.02 8.47 20.65UNK_AI844520 AI844520 97527_at 0.00 4.63 5.52 9.52 8.69 5.59UNK_AA681998 AA681998 97838_at 0.00 2.19 3.16 3.46 5.45 3.88UNK_AA684508 AA684508 98076_at 0.00 2.21 3.02 6.55 5.41 5.24UNK_AI835644 AI835644 98915_at 0.00 5.42 4.17 5.26 4.08 4.94UNK_AI849082 AI849082 99849_at 0.00 2.58 2.39 3.64 2.12 4.11 UNK_C85523C85523 100116_at 0.00 3.92 4.43 5.52 8.26 3.36 UNK_AI122538 AI122538100511_at 0.00 3.60 4.84 3.90 2.10 3.63 UNK_AI154249 AI154249 101061_at0.00 2.33 2.52 5.11 5.20 4.85 UNK_AI845293 AI845293 101464_at 1.63 7.866.79 16.41 14.96 19.13 metalloproteinase; V00755 Timp 101912_at 0.004.12 4.68 7.62 13.31 6.66 UNK_AI019679 AI019679 101956_at 0.00 4.37 3.277.15 8.46 8.94 UNK_AI834849 AI834849 102056_f_at 0.00 2.01 2.37 3.494.61 4.59 UNK_AA839379 AA839379 102108_f_at 0.00 2.23 2.51 3.59 3.193.25 UNK_AI505453 AI505453 102907_at 0.00 2.60 6.00 11.32 13.64 4.29UNK_AW125043 AW125043 103017_at 0.00 2.12 3.20 5.24 4.49 20.95 D13ABB1EAI060729 103723_at 0.00 2.32 2.67 3.04 3.60 3.21 0 AA608387 104023_at0.00 2.89 3.42 5.91 4.20 5.95 UNK_AW060457 AW060457 104389_at 0.00 2.653.70 4.62 5.54 7.36 UNK_AW049360 AW049360 104464_s_at 0.00 2.24 3.4810.84 18.75 9.30 UNK_AI642389 AI642389 105606_at 1.75 2.68 2.44 2.776.16 5.68 UNK_AW210072 AW210072 105881_at 0.00 2.16 2.37 3.53 5.35 24.32UNK_AI847606 AI847606 106310_at 0.00 3.45 3.22 2.71 2.82 3.11UNK_AI843606 AI843606 106619_at 2.41 2.32 0.00 2.78 3.02 3.67UNK_AW060770 AW060770 107510_at 0.00 8.81 6.27 8.47 8.55 5.39UNK_AW049506 AW049506 107935_at 0.00 2.29 4.62 10.35 26.40 9.69UNK_AI450518 AI450518 108018_at 0.00 2.98 3.50 5.18 16.34 11.82UNK_AA959436 AA959436 108477_at 0.00 3.49 3.67 6.12 15.44 10.74UNK_AA692253 AA692253 109103_f_at 0.00 2.58 3.05 3.95 4.48 3.00UNK_AI841088 AI841088 109669_at 0.00 2.64 3.10 5.19 15.50 11.17UNK_AA796759 AA796759 109737_at 0.00 3.30 3.69 7.52 10.54 18.42UNK_AI836805 AI836805 109982_at 0.00 3.10 2.97 3.92 5.94 12.35UNK_AI851247 AI851247 110160_at 0.00 3.54 6.56 5.47 2.73 3.51UNK_AI510217 AI510217 110187_at 0.00 2.20 2.36 2.56 2.44 3.74UNK_AA624041 AA624041 110334_at 0.00 2.05 2.27 6.10 4.52 6.30UNK_AI852289 AI852289 110848_at 0.00 3.74 4.17 8.73 18.05 9.18UNK_AI851487 AI851487 111125_at 0.00 2.32 2.83 2.54 3.64 7.94UNK_AI391368 AI391368 111225_at 0.00 2.83 2.56 3.59 6.73 3.30UNK_AW121825 AW121825 111350_at 0.00 2.33 3.71 2.48 5.40 4.17UNK_AI462022 AI462022 111841_at 0.00 3.34 4.66 5.84 4.01 7.21UNK_AI527656 AI527656 112039_at 0.00 2.69 2.34 2.25 2.25 3.88UNK_AA178128 AA178128 112322_at 0.00 3.84 2.74 2.31 2.17 3.75UNK_AA931004 AA931004 112383_at 0.00 2.92 5.72 9.18 4.14 6.63UNK_AI155444 AI155444 112687_at 0.00 2.10 2.91 2.49 3.33 3.44UNK_AA683840 AA683840 112763_at 0.00 3.08 2.52 3.95 5.44 2.31UNK_AI788757 AI788757 112807_at 0.00 2.55 3.32 3.33 5.30 3.44UNK_AI891565 AI891565 113750_at 1.90 3.09 3.33 3.67 2.95 4.78UNK_AA881110 AA881110 113932_g_at 0.00 3.21 3.06 5.89 6.81 3.86UNK_AW230677 AW230677 114025_at 1.61 6.05 10.16 14.50 25.81 11.77UNK_AI643935 AI643935 114303_at 1.50 8.14 14.58 11.85 13.19 2.02UNK_AW107218 AW107218 114498_at 0.00 3.36 3.84 3.78 4.04 3.68UNK_AW215808 AW215808 114701_at 1.81 2.80 2.37 5.00 12.96 7.64UNK_AI425702 AI425702 116159_at 0.00 3.76 4.87 3.67 2.28 3.06UNK_AA823048 AA823048 116414_at 0.00 3.28 3.48 5.32 3.90 7.35UNK_AI180528 AI180528 116943_at 0.00 2.38 2.30 4.09 3.55 4.14UNK_AI852450 AI852450 116969_at 0.00 2.04 2.14 2.52 2.63 3.29UNK_AI843050 AI843050 117049_at 0.00 2.11 2.62 2.33 2.62 3.41UNK_AI848494 AI848494 135169_at 0.00 2.79 3.47 3.44 2.37 2.14UNK_AA509929 AA509929 137100_at 2.43 4.34 4.00 4.39 1.80 3.84UNK_AW214591 AW214591 139422_at 0.00 2.58 3.05 5.10 2.06 3.16UNK_AW212694 AW212694 92185_at 0.00 0.00 2.80 3.37 5.13 2.63UNK_AI846023 AI846023 92787_at 0.00 2.76 0.00 2.66 3.64 2.18UNK_AI845902 AI845902 92800_i_at 0.00 1.89 2.06 3.12 3.93 5.57UNK_AI836694 AI836694 93037_i_at 0.00 2.22 0.00 3.35 2.89 4.40 LPC1M69260 93327_at 0.00 0.00 4.87 5.05 4.80 4.81 UNK_AI842665 AI84266594273_at 0.00 1.93 2.18 4.60 6.39 4.24 UNK_AI849067 AI849067 94330_at0.00 5.76 2.95 4.18 2.28 0.00 UNK_AA710564 AA710564 94486_at 0.00 1.872.21 3.22 3.76 2.56 UNK_AW125178 AW125178 94549_at 0.00 2.24 0.00 2.482.75 2.12 UNK_AI315650 AI315650 94830_at 0.00 2.01 0.00 2.55 2.23 2.09UNK_AI854300 AI854300 94992_at 0.00 1.93 2.08 3.30 5.15 4.11UNK_AI840667 AI840667 95590_at 0.00 0.00 2.08 3.19 3.55 4.06UNK_AA615951 AA615951 95648_at 0.00 1.92 2.17 2.65 2.60 3.36UNK_AA655507 AA655507 95885_at 0.00 1.53 2.21 3.06 3.95 2.16UNK_AA177621 AA177621 96004_at 0.00 6.08 0.00 5.08 7.87 7.33UNK_AI851641 AI851641 96262_at 0.00 4.44 3.02 1.84 2.66 3.32UNK_AI836812 AI836812 96605_at 0.00 1.99 8.89 9.27 26.99 8.68UNK_AI787183 AI787183 96708_at 0.00 1.59 2.40 3.97 4.47 4.62UNK_AW120643 AW120643 97211_at 0.00 0.00 2.92 5.48 8.89 5.70UNK_AI747444 AI747444 97425_at 0.00 3.99 4.68 0.00 15.01 10.66UNK_AI840191 AI840191 97456_at 0.00 3.00 1.91 3.34 2.85 4.04UNK_AI838021 AI838021 97811_at 0.00 2.45 0.00 6.99 21.66 12.97UNK_AI844507 AI844507 97947_at 0.00 1.70 2.19 2.39 2.35 3.32UNK_AI836959 AI836959 97964_at 0.00 0.00 4.12 10.11 19.39 10.90UNK_AW122851 AW122851 98107_at 0.00 1.89 2.26 4.29 5.16 5.87UNK_AW123801 AW123801 98346_at 0.00 0.00 2.40 3.53 8.88 9.07UNK_AI593759 AI593759 98440_at 0.00 0.00 3.53 3.85 3.62 3.27UNK_AA596710 AA596710 99149_at 0.00 1.63 2.59 2.83 3.43 2.04UNK_AI851230 AI851230 99191_at 0.00 1.66 2.04 2.42 2.86 2.36UNK_AI844939 AI844939 99366_at 0.00 1.74 2.18 2.99 3.04 7.11UNK_AI553536 AI553536 99505_at 0.00 2.50 0.00 4.22 2.83 2.64UNK_AI844664 AI844664 100611_at 0.00 1.75 2.16 2.76 2.14 3.06 lysozyme;Lyzs M21050 102936_at 0.00 2.24 2.95 2.51 2.80 0.00 UNK_AW125314AW125314 103435_at 0.00 2.05 0.00 4.32 4.31 6.16 UNK_AW045910 AW045910103525_at 0.00 0.00 2.54 2.48 2.46 2.26 UNK_AA981725 AA981725 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0.00 0.00 0.00 0.00 1.43 4.48UNK_AI838644 AI838644 112082_at 0.00 0.00 0.00 0.00 5.39 0.00UNK_AI591941 AI591941 112091_at 0.00 0.00 0.00 0.00 4.52 0.00UNK_AI426016 AI426016 112167_f_at 0.00 0.00 0.00 0.00 2.50 0.00UNK_W96857 W96857 112209_at 0.00 0.00 0.00 0.00 2.64 0.00 UNK_AW122818AW122818 112269_at 0.00 0.00 0.00 0.00 1.77 2.67 UNK_AW123962 AW123962112291_r_at 0.00 1.64 1.80 0.00 2.57 1.43 UNK_AA655542 AA655542112333_at 0.00 0.00 0.00 2.17 0.00 0.00 UNK_AI835570 AI835570 112338_at0.00 0.00 0.00 0.00 3.04 0.00 UNK_AI846227 AI846227 112402_at 0.00 0.000.00 0.00 2.30 0.00 UNK_AW045953 AW045953 112404_at 0.00 0.00 0.00 0.002.70 0.00 UNK_AI844302 AI844302 112488_at 0.00 0.00 0.00 0.00 1.88 3.93UNK_AW120970 AW120970 112499_at 0.00 0.00 0.00 0.00 4.01 0.00UNK_AI172791 AI172791 112652_at 0.00 0.00 0.00 0.00 3.04 0.00UNK_AA636643 AA636643 112703_at 0.00 0.00 0.00 0.00 2.26 0.00UNK_AI846613 AI846613 112729_at 0.00 0.00 0.00 0.00 1.50 2.17UNK_AA644819 AA644819 112733_at 0.00 4.52 0.00 0.00 0.00 0.00UNK_AW212343 AW212343 112795_at 0.00 0.00 0.00 1.99 1.74 2.51UNK_AI854434 AI854434 112827_at 0.00 0.00 0.00 2.50 0.00 0.00UNK_AI847696 AI847696 112847_at 0.00 0.00 0.00 0.00 5.12 0.00UNK_AW123508 AW123508 112857_g_at 0.00 0.00 0.00 0.00 1.74 3.22UNK_AI852143 AI852143 112981_at 0.00 0.00 0.00 0.00 3.36 0.00UNK_AW060744 AW060744 112989_at 0.00 0.00 0.00 0.00 2.84 0.00UNK_AA940527 AA940527 113018_at 0.00 0.00 0.00 0.00 2.51 0.00UNK_AA855540 AA855540 113021_at 0.00 0.00 0.00 1.68 1.90 2.98UNK_AI840910 AI840910 113027_at 0.00 0.00 0.00 0.00 2.41 1.83UNK_AA816040 AA816040 113043_at 0.00 1.39 2.10 1.81 1.90 0.00UNK_AI429002 AI429002 113119_at 0.00 0.00 0.00 2.06 0.00 0.00UNK_AI835854 AI835854 113186_at 0.00 0.00 0.00 0.00 1.98 2.98UNK_AI852046 AI852046 113226_at 0.00 0.00 0.00 0.00 1.46 2.36UNK_AW230690 AW230690 113228_at 0.00 0.00 0.00 3.05 0.00 0.00UNK_AW120751 AW120751 113239_at 0.00 0.00 0.00 0.00 2.39 0.00UNK_AW213684 AW213684 113285_at 0.00 0.00 0.00 0.00 5.51 0.00UNK_AI850452 AI850452 113288_at 0.00 0.00 1.97 0.00 1.78 3.18UNK_AA967846 AA967846 113328_at 0.00 0.00 0.00 1.93 1.72 2.18UNK_AW214631 AW214631 113333_at 0.00 0.00 1.64 1.58 1.86 2.27UNK_AA793994 AA793994 113443_r_at 0.00 0.00 0.00 1.85 2.32 0.00UNK_AI429737 AI429737 113541_at 0.00 0.00 0.00 2.43 0.00 0.00UNK_AI843578 AI843578 113548_at 0.00 0.00 0.00 0.00 2.22 1.41UNK_AI844170 AI844170 113550_at 0.00 0.00 0.00 0.00 2.03 0.00UNK_AI846429 AI846429 113574_at 0.00 0.00 0.00 0.00 3.35 0.00UNK_AW049388 AW049388 113620_at 0.00 0.00 0.00 0.00 4.93 0.00UNK_AW047525 AW047525 113629_at 0.00 0.00 0.00 0.00 2.74 0.00UNK_AW047341 AW047341 113656_at 0.00 0.00 0.00 0.00 2.02 0.00UNK_AW050247 AW050247 113657_at 0.00 0.00 0.00 0.00 2.44 0.00UNK_AW048440 AW048440 113695_at 0.00 0.00 0.00 0.00 4.37 0.00UNK_AW120861 AW120861 113728_at 0.00 0.00 0.00 0.00 1.99 2.07UNK_AA915716 AA915716 113777_at 0.00 0.00 1.73 1.61 1.91 3.04UNK_AW048627 AW048627 113863_at 0.00 0.00 0.00 0.00 3.00 0.00UNK_AA014260 AA014260 113896_at 0.00 0.00 0.00 1.74 2.37 0.00UNK_AI425640 AI425640 114001_at 0.00 2.63 0.00 0.00 0.00 0.00UNK_AW211307 AW211307 114102_at 0.00 1.37 0.00 1.47 1.81 2.47UNK_AW061165 AW061165 114140_at 0.00 0.00 0.00 0.00 2.55 0.00UNK_AW214473 AW214473 114168_at 0.00 0.00 0.00 0.00 2.43 0.00UNK_AW121266 AW121266 114323_at 0.00 0.00 0.00 0.00 3.13 0.00UNK_AA756403 AA756403 114379_at 0.00 0.42 2.02 1.46 0.00 0.00UNK_AI050351 AI050351 114461_at 0.00 0.00 1.58 1.62 2.81 0.00UNK_AI874945 AI874945 114525_at 0.00 1.28 0.00 0.00 2.05 1.73UNK_AA290482 AA290482 114667_at 0.00 0.00 0.00 0.00 2.62 1.66UNK_AA399878 AA399878 114695_at 0.00 0.00 2.00 0.00 0.00 0.00UNK_AI842428 A1842428 114698_at 0.00 0.00 0.00 2.51 0.00 0.00UNK_AW120476 AW120476 114709_at 0.00 0.00 0.00 0.00 2.24 0.00UNK_AI847047 AI847047 114718_at 0.00 0.00 0.00 0.00 2.28 0.00UNK_AI267112 AI267112 114747_at 0.00 0.00 0.00 2.24 1.87 0.00UNK_AI851384 AI851384 114830_at 0.00 0.00 0.00 1.59 1.90 2.41UNK_AI847957 AI847957 114880_at 0.00 0.00 2.18 1.92 1.39 1.80UNK_AW123237 AW123237 114955_at 0.00 0.00 0.00 0.00 1.75 2.50UNK_AI314760 AI314760 114996_at 0.00 0.00 0.00 0.00 2.00 0.00UNK_AA967301 AA967301 115032_i_at 0.00 0.00 0.00 1.76 2.89 1.84UNK_AI848847 AI848847 115064_at 0.00 0.00 0.00 0.00 2.36 0.00UNK_AI573356 AI573356 115091_at 0.00 0.00 0.00 3.34 0.00 0.00UNK_AA647787 AA647787 115093_at 0.00 0.00 0.00 0.00 1.90 3.27UNK_AI606104 AI606104 115112_at 0.00 0.00 0.00 0.00 5.07 0.00UNK_AW050362 AW050362 115140_at 0.00 0.00 0.00 0.00 2.84 0.00UNK_AW124719 AW124719 115153_at 0.00 0.00 0.00 0.00 1.70 2.94UNK_AI789647 AI789647 115195_at 0.00 0.00 0.00 1.66 11.32 0.00UNK_AI838694 AI838694 115212_at 0.00 0.00 0.00 2.24 0.00 0.00UNK_AA856478 AA856478 115266_at 0.00 0.00 0.00 0.00 3.97 0.00UNK_AI152744 AI152744 115333_at 0.00 0.00 0.00 1.27 6.94 0.00UNK_AI593245 AI593245 115338_at 0.00 0.00 2.06 0.00 0.00 0.00UNK_AI158964 AI158964 115354_at 0.00 0.00 0.00 0.00 3.71 0.00UNK_AA895031 AA895031 115371_at 0.00 0.00 0.00 0.00 1.99 7.39UNK_AI465535 AI465535 115402_at 0.00 0.00 0.00 0.00 2.68 0.00UNK_AW120513 AW120513 115416_at 0.00 0.00 0.00 0.00 3.28 0.00UNK_AA645547 AA645547 115449_at 0.00 0.00 0.00 0.00 1.77 5.16UNK_AW049627 AW049627 115481_at 0.00 0.00 0.00 0.00 2.75 0.00UNK_AI256692 AI256692 115506_at 0.00 0.00 0.00 0.00 1.60 2.05UNK_AW048699 AW048699 115652_at 0.00 2.11 0.00 1.53 0.00 0.00UNK_AI450439 AI450439 115885_at 0.00 0.00 0.00 0.00 2.93 0.00UNK_AW211469 AW211469 115891_at 0.00 0.00 0.00 0.00 1.97 2.64UNK_AI481691 AI481691 115898_at 0.00 0.00 0.00 0.00 3.98 0.00UNK_AA739008 AA739008 115904_at 0.00 0.00 0.00 0.00 1.82 2.84UNK_AI788994 AI788994 115916_at 0.00 0.00 0.00 0.00 1.32 2.42UNK_AA691429 AA691429 115917_at 0.00 0.00 1.70 1.88 2.26 0.00UNK_AA874421 AA874421 116044_at 0.00 0.00 0.00 1.94 2.10 0.00UNK_AA824110 AA824110 116102_at 0.00 0.00 0.00 0.00 3.55 0.00UNK_AW261562 AW261562 116139_at 0.00 0.00 0.00 0.00 3.24 0.00UNK_AA838903 AA838903 116166_at 0.00 0.00 0.00 0.00 1.95 3.46UNK_AI853928 AI853928 116286_at 0.00 0.00 0.00 2.20 1.92 0.00UNK_AI553581 AI553581 116320_at 0.00 0.00 0.00 0.00 1.60 3.82UNK_AW124054 AW124054 116345_at 0.00 0.00 1.80 1.61 2.25 0.00UNK_AI854429 AI854429 116379_at 0.00 0.00 0.00 0.00 2.14 0.00UNK_AA178683 AA178683 116386_at 0.00 0.00 0.00 0.00 3.10 0.00UNK_AA981888 AA981888 116426_at 0.00 0.00 0.00 0.00 2.50 0.00UNK_AW212535 AW212535 116431_at 0.00 0.00 0.00 0.00 2.17 0.00UNK_AI316839 AI316839 116451_at 0.00 0.00 0.00 0.00 4.73 1.71UNK_AA615200 AA615200 116562_at 0.00 2.64 0.00 0.00 0.00 0.00UNK_AI451360 AI451360 116576_at 0.00 0.00 0.00 0.00 1.76 2.03UNK_AI451563 AI451563 116582_at 0.00 0.00 0.00 0.00 2.90 0.00UNK_AI987726 AI987726 116671_at 0.00 0.00 0.00 0.00 1.75 2.22UNK_AW123023 AW123023 116831_at 0.00 0.00 0.00 0.00 2.29 0.00UNK_AI747220 AI747220 116858_at 0.00 0.00 1.49 1.78 1.76 7.51 MAFBAI849704 116955_at 0.00 0.00 0.00 0.00 2.46 0.00 UNK_AI847605 AI847605116986_at 0.00 0.00 0.00 0.00 2.28 0.00 UNK_AW120935 AW120935 117186_at0.00 1.72 1.60 2.17 1.62 0.00 UNK_AI847496 AI847496 117196_at 0.00 0.000.00 0.00 1.80 4.64 UNK_AI840220 AI840220 117218_at 0.00 0.00 0.00 0.003.04 0.00 UNK_AI848424 AI848424 117235_at 0.00 1.18 0.00 1.34 2.48 0.00UNK_AI843866 AI843866 117260_at 0.00 0.00 0.00 0.00 4.03 0.00UNK_AI841583 AI841583 117276_at 0.00 0.00 0.00 0.00 2.92 0.00UNK_AI849085 AI849085 117310_at 0.00 0.00 0.00 0.00 3.99 0.00UNK_AI835269 AI835269 129180_f_at 0.00 0.00 0.00 0.00 1.87 3.06UNK_AW214234 AW214234 129925_at 0.00 0.00 0.00 0.00 1.88 3.42UNK_AW212719 AW212719 129983_at 0.00 1.93 1.73 3.10 1.52 1.45UNK_AA795716 AA795716 130549_f_at 0.00 6.37 0.00 0.00 0.00 0.00UNK_AU018276 AU018276 130719_at 0.00 0.00 0.00 1.99 1.42 4.14UNK_AW045814 AW045814 130804_at 0.00 0.00 0.00 1.73 2.86 0.00UNK_AU024135 AU024135 132172_at 0.00 0.00 2.03 1.88 0.00 0.00UNK_AI195127 AI195127 132364_i_at 0.00 0.00 0.00 0.00 2.40 0.00UNK_AI594430 AI594430 132365_r_at 0.00 0.00 0.00 0.00 1.89 2.06UNK_AI594430 AI594430 133139_at 0.00 0.00 0.00 3.87 1.76 0.00UNK_AW122295 AW122295 133799_at 0.00 0.00 0.00 0.00 4.06 0.00UNK_AI131700 AI131700 133901_f_at 0.00 0.00 0.00 1.64 0.46 2.10UNK_AI481837 A1481837 134388_at 0.00 1.21 0.00 0.00 1.88 2.31UNK_AI536536 AI536536 134515_at 0.00 0.00 0.00 0.00 1.93 2.29UNK_AI874652 AI874652 134531_at 0.00 0.00 0.00 0.00 4.11 1.62UNK_AW121822 AW121822 134597_at 0.00 0.00 0.00 0.00 4.14 0.00UNK_AI643832 AI643832 134660_at 0.00 0.00 0.00 2.17 1.73 0.00UNK_AA793588 AA793588 134662_f_at 0.00 0.00 0.00 2.20 1.47 1.48UNK_AI585590 AI585590 135172_at 0.00 0.00 0.00 0.00 1.32 2.79UNK_AI480578 AI480578 135314_at 0.00 0.00 1.79 1.78 2.48 2.00UNK_AI842058 AI842058 135355_at 0.00 0.00 0.00 0.00 1.91 3.47UNK_AW228646 AW228646 135552_f_at 0.00 2.62 0.00 0.00 0.00 0.00UNK_AI646499 AI646499 135655_at 0.00 0.00 0.00 2.23 0.00 0.00UNK_AI447921 AI447921 135812_at 0.00 0.00 0.00 0.00 2.23 0.00UNK_AI848262 AI848262 135888_at 0.00 0.00 0.00 1.83 1.89 2.00UNK_AI153331 AI153331 136132_at 0.00 1.92 2.10 1.78 0.00 0.00UNK_AI853191 AI853191 136191_at 0.00 2.22 0.00 0.00 0.00 0.00UNK_AI852455 AI852455 136558_at 0.00 0.00 0.00 0.00 1.01 2.20UNK_AI465462 AI465462 137699_at 0.00 2.23 0.00 0.00 1.35 0.00UNK_AW045500 AW045500 138079_at 0.00 0.00 0.00 0.00 1.62 2.50UNK_AI849673 AI849673 138945_at 0.00 2.27 0.11 0.00 0.00 0.00UNK_AI843433 AI843433 138960_f_at 0.00 0.00 0.00 0.00 1.25 2.04UNK_AI841128 AI841128 140441_at 0.00 2.51 0.00 0.00 0.00 0.00UNK_AW105899 AW105899 140654_at 0.00 0.00 0.00 0.00 1.49 2.03UNK_AA967374 AA967374 140760_at 0.00 0.00 0.00 0.00 2.05 0.00UNK_AI648116 AI648116 140893_at 0.00 0.00 0.00 1.17 2.24 0.00UNK_AW123714 AW123714 140999_at 0.00 1.68 1.97 2.74 1.61 1.53UNK_AA561076 AA561076 141179_at 0.00 2.26 0.00 0.00 0.00 0.00UNK_AI645500 AI645500 97543_at 0.00 0.00 0.00 2.96 1.83 2.01 expressed,D49382 developmentally down-regulated gene 5; Nedd5 96337_at 0.00 0.000.00 0.00 6.05 6.35 PNUTL1 AF033350 98609_at 0.00 0.00 0.00 3.74 5.094.97 MSF AJ250723 98149_s_at 0.00 2.78 2.86 6.13 9.13 4.99 UNK_AW046496AW046496 110272_at 0.00 2.06 5.37 4.90 3.35 3.49 UNK_AA636558 AA63655892459_at 0.00 4.73 9.59 15.62 24.77 14.53 UNK_AB023418 AB023418 97198_at0.00 0.00 0.00 3.04 2.54 4.37 cassette, sub-family X75926 A (ABC1),member 1; Abca1 103035_at 0.00 1.73 2.92 4.20 2.83 4.90 TAP1 U6002098402_at 0.00 0.00 0.00 2.12 2.32 2.07 ACLP7 AI843799 92688_at 0.00 2.012.65 2.91 2.26 2.58 acid phosphatase 2, X57199 lysosomal; Acp2 97904_at0.00 1.93 1.98 3.64 2.94 3.68 UNK_AW123953 AW123953 96573_at 0.00 1.690.00 2.54 1.91 2.14 actin, gamma, M21495 cytoplasmic, actin- like; Actg,Actl 96343_at 0.00 1.72 1.82 3.41 3.64 3.03 UNK_AI836968 AI83696893100_at 0.00 0.00 0.00 3.39 4.40 2.27 vascular smooth X13297 muscle;Actvs 93460_at 0.00 0.00 0.00 0.00 2.49 1.93 activin A receptor, L15436type 1; Acvr1 100751_at 0.00 0.00 0.00 0.00 2.25 2.76 metalloproteaseAF011379 domain (ADAM) 10; Adam10 92414_at 0.00 1.50 0.00 5.97 9.93 8.83a disintegrin and D50411 metalloproteinase domain 12 (meltrin alpha);Adam12 103554_at 0.00 0.00 2.63 3.50 5.47 3.45 a disintegrin andAA726223 metalloproteinase domain 19 (meltrin beta); Adam 19 103024_at6.28 10.02 5.98 4.43 4.10 2.38 ADAM8 X13335 103392_at 0.00 0.00 2.423.39 3.92 3.18 adenylate cyclase 7; U12919 Adcy7 94535_at 0.00 0.00 0.000.00 2.19 0.00 ADD1 AW121844 100903_at 0.00 0.00 0.00 2.36 1.77 1.90ADPRT2 AJ007780 99038_at 0.00 0.00 0.00 3.40 4.12 3.85 adenylosuccinateL24554 synthetase 2, non muscle; Adss2 99039_g_at 0.00 1.47 0.00 2.782.26 2.44 adenylosuccinate L24554 synthetase 2, non muscle; Adss2100412_g_at 0.00 0.00 0.00 2.85 2.62 0.00 AEBP1 AF053943 136586_at 0.003.12 3.56 5.26 6.60 6.27 UNK_AA960336 AA960336 96357_at 0.00 1.61 1.852.83 3.78 4.62 AF007010 AW212775 104205_at 0.00 0.00 0.00 3.25 19.164.89 aggrecan, structural L07049 proteoglycan of cartilage; Agc 92210_at0.00 0.00 0.00 0.00 2.69 7.02 Agpt2 AF004326 96025_g_at 0.00 0.00 2.182.51 0.00 0.00 adenosylhomocysteine L32836 hydrolase; Ahcy 103551_at0.00 0.00 0.00 0.00 2.39 4.11 UNK_AW124208 AW124208 116577_at 0.00 0.000.00 0.00 2.86 3.71 UNK_AI450355 AI450355 107536_at 0.00 0.00 2.87 4.473.94 4.08 UNK_AI851964 AI851964 104415_at 0.00 0.00 0.00 0.00 2.85 0.00UNK_AA833293 AA833293 103911_at 0.00 0.00 0.00 0.00 2.57 2.19UNK_AI851573 AI851573 102330_at 2.21 4.90 6.74 9.69 5.41 3.36 AIF1D86382 103443_at 0.00 2.98 0.00 0.00 2.23 0.00 UNK_AA711704 AA71170495148_at 0.00 0.00 1.83 3.07 3.90 5.63 AK2 AB020202 92796_at 0.00 0.004.88 10.36 57.57 19.90 phosphatase 2, liver; J02980 Akp2 96888_at 0.000.00 0.00 2.21 2.04 2.03 UNK_AI839814 AI839814 100970_at 0.00 0.00 0.002.56 2.72 2.86 thymoma viral proto- X65687 oncogene; Akt 98372_at 0.002.97 0.00 5.29 2.86 0.00 UNK_AW050387 AW050387 96243_f_at 0.00 1.81 0.000.00 2.32 3.58 UNK_AW120804 AW120804 102048_at 4.83 7.77 16.74 18.4810.36 4.40 ALRP AF041847 94392_f_at 0.00 2.01 1.70 2.55 2.32 0.00angiogenin; Ang U22516 102054_at 0.00 2.71 0.00 2.96 2.56 2.75 ANKHZNAB011370 93038_f_at 0.00 2.05 2.40 3.64 3.20 3.58 LPC1 M69260 100569_at2.07 2.76 2.79 4.54 4.52 4.67 annexin A2; Anxa2 M14044 101393_at 2.430.00 0.00 2.45 2.13 0.00 ANXA3 AJ001633 100584_at 0.00 0.00 1.67 2.842.85 4.02 annexin A4; Anxa4 U72941 93083_at 0.00 0.00 0.00 2.67 2.692.86 ANXA5 D63423 93587_at 0.00 0.00 0.00 3.45 0.00 0.00 annexin A7;Anxa7 L13129 97529_at 0.00 2.06 0.00 5.97 8.79 7.30 annexin A8; Anxa8AJ002390 102327_at 0.00 0.00 2.07 2.55 3.01 3.11 AOC3 AF078705 103242_at0.00 0.00 0.00 1.94 2.49 2.90 UNK_AW123834 AW123834 103878_at 0.00 0.000.00 2.13 2.21 2.07 AP3B1 AF103809 103796_at 0.00 0.00 0.00 3.99 3.273.46 APAF1 AF064071 102710_at 2.15 2.86 3.37 3.90 3.45 5.22 precursorprotein- AF020313 binding, family B, member 1 interacting protein; Apbb1ip-pending 101035_at 0.00 0.00 2.01 0.00 1.84 2.15 apoptosis inhibitor5; U35846 Api5 98398_s_at 0.00 2.97 3.11 3.55 2.15 2.64 APOBEC1 U2226295356_at 0.00 1.46 1.78 2.38 2.50 3.08 Apoe D00466 93700_at 0.00 0.000.00 0.00 2.47 2.59 SIAT9 AI838022 96587_at 0.00 0.00 0.00 0.00 3.152.61 ADP-ribosylation D87900 factor 3; Arf3 92968_at 0.00 0.00 0.00 0.002.14 0.00 ADP-ribosylation D87902 factor 5; Arf5 93097_at 0.00 6.15 1.741.71 0.00 0.00 Arg1 U51805 101030_at 0.00 0.00 0.00 1.85 2.12 3.24homolog B (RhoB); X99963 Arhb 96056_at 0.00 0.00 0.00 3.00 3.64 4.22homolog 9 (RhoC); X80638 Arhc 95547_at 0.00 0.00 0.00 0.00 5.84 3.99homolog D (RhoD); D89821 Arhd 98001_at 0.00 0.00 2.06 1.83 2.85 2.92nucleotide exchange U58203 factor (GEF) 1; Arhgef1 101439_at 0.00 0.000.00 0.00 2.72 2.07 UNK_AW122716 AW122716 115479_at 0.00 0.00 2.38 5.555.94 3.35 ARP2-PENDING AA792177 95434_at 0.00 2.17 2.13 2.92 2.24 2.57UNK_AI851740 AI851740 100931_at 0.00 0.00 0.00 0.00 4.46 4.79arylsulfatase A; As2 X73230 94282_at 0.00 1.86 0.00 3.66 3.84 3.64UNK_AW124297 AW124297 95133_at 0.00 0.00 0.00 0.00 5.31 0.00 asparagineU38940 synthetase; Asns 101984_at 0.00 0.00 0.00 1.79 2.04 2.76 ATX1(antioxidant AF004591 protein 1) homolog 1 (yeast); Atox1 99579_at 0.001.58 0.00 2.44 2.72 3.30 beta 3 polypeptide; U59761 Atp1b3 98126_s_at0.00 0.00 0.00 0.00 2.12 0.00 ATPase, Ca++ X67140 transporting, cardiacmuscle, fast twitch 1; Atp2a1 95746_at 0.00 1.51 0.00 2.69 2.20 7.69ATP6A2 AW123765 95745_g_at 0.00 1.35 0.00 1.80 1.68 6.74 transporting,U13837 lysosomal (vacuolar proton pump), alpha 70 kDa, isoform 2;94301_at 0.00 2.37 2.07 3.22 5.34 8.96 ATP6K AI843269 102854_s_at 0.002.19 0.00 0.00 0.00 0.00 ATPase, Cu++ U03434 transporting, alphapolypeptide; Atp7a 93984_at 0.00 1.88 2.24 3.26 3.23 3.67 Atpi AF00271898960_s_at 0.00 0.00 0.00 1.73 2.48 1.89 UNK_AF029792 AF029792 103002_at0.00 0.00 0.00 1.95 2.15 1.84 B4GALT1 M27923 104005_at 0.00 0.00 0.000.00 5.00 2.43 B4GALT2 AB019541 111981_at 0.00 0.00 0.00 0.00 2.02 0.00BACE2 AW122959 99670_at 0.00 0.00 0.00 0.00 3.45 2.81 Bcl-associateddeath L37296 promoter; Bad 93536_at 0.00 0.00 0.00 3.00 3.22 2.81Bcl2-associated X L22472 protein; Bax 93252_at 0.00 0.00 0.00 0.00 2.570.00 B-cell receptor- X81816 associated protein 31; Bcap31 100026_at0.00 0.00 0.00 5.43 16.18 0.00 BCAT1 U42443 94448_at 0.00 0.00 0.00 2.851.58 2.13 BCL10 AJ006289 102914_s_at 0.00 0.00 0.00 0.00 5.13 13.02BCL2A1B U23778 93869_s_at 0.00 0.00 0.00 2.68 3.36 9.35 BCL2A1D U23781101748_at 0.00 0.00 0.00 0.00 13.92 0.00 bradykinin receptor, U47281beta; Bdkrb 101514_at 0.00 0.00 0.00 2.06 3.68 2.34 BET3-PENDINGAF041433 103647_at 0.00 0.00 3.61 2.66 5.42 16.86 beta-galactosidaseM57734 complex; Bgl 96049_at 0.00 2.06 2.40 4.02 3.69 4.37 BGN X5392898433_at 0.00 2.16 0.00 0.00 1.45 2.01 domain death U75506 agonist; Bid101521_at 0.00 4.32 4.05 5.67 5.14 3.35 AP14 AB013819 95803_at 0.00 3.170.00 3.77 3.63 5.29 BIT D85785 95804_g_at 0.00 5.17 0.00 0.00 8.80 10.32BIT D85785 93604_f_at 0.00 0.00 0.00 0.00 2.95 14.19 BL2 AF06126093606_s_at 0.00 0.00 0.00 0.00 3.11 11.25 BL2 AB021966 95557_at 0.000.00 0.00 6.05 10.83 17.24 bone morphogenetic L24755 protein 1; Bmp192701_at 0.00 0.00 0.00 0.00 8.10 7.21 BMP1 AA518586 95012_at 0.00 0.000.00 0.00 1.54 4.40 UNK_AB012808 AB012808 98031_at 0.00 0.00 0.00 0.009.58 0.00 BOKL-PENDING AF027707 94036_at 0.00 0.00 0.00 0.00 5.14 4.93UNK_AI844806 AI844806 93324_at 0.00 0.00 0.00 3.98 3.49 3.40 butyrateresponse M58566 factor 1; Brf1 93104_at 0.00 2.95 2.80 4.02 4.75 5.01BTG1 Z16410 96146_at 0.00 0.00 0.00 3.56 6.34 5.24 BTG3 D83745 104097_at0.00 0.00 1.72 2.12 1.86 0.00 budding uninhibited AF002823 bybenzimidazoles 1 homolog (S. cerevisiae); Bub1 109165_at 0.00 0.00 0.000.00 2.63 0.00 BUB1B AW049504 93042_at 0.00 1.80 0.00 2.82 2.69 3.24benzodiazepine D21207 receptor, peripheral; Bzrp 96718_at 0.00 0.00 0.000.00 1.79 2.12 UNK_AB012727 AB012727 98562_at 0.00 2.80 3.66 5.77 3.764.31 component 1, q X58861 subcomponent, alpha polypeptide; 96020_at0.00 2.88 4.26 6.67 4.45 4.01 component 1, q M22531 subcomponent, betapolypeptide; C1qb 92223_at 0.00 1.85 2.43 4.07 2.93 2.85 component 1, qX66295 subcomponent, c polypeptide; C1qc 103707_at 0.00 2.61 3.37 4.053.10 2.93 C3AR1 U77461 103033_at 0.00 0.00 1.67 2.36 3.44 3.66 C4 X06454101728_at 0.00 2.20 0.00 0.12 3.09 0.00 C5R1 S46665 98483_at 0.00 0.000.00 0.00 5.67 7.91 CACNB3 X94404 95423_at 0.00 2.15 2.96 5.11 3.94 3.37CAI Y00884 100155_at 3.86 2.01 2.63 4.29 1.65 0.00 Cak L57509 101107_at0.00 0.00 0.00 3.14 3.16 2.78 calumenin; Calu U81829 104529_at 0.00 0.001.88 1.93 2.26 2.09 calcium modulating U21960 ligand; Caml 101040_at0.00 1.47 1.28 2.06 1.74 2.07 calpain 2; Capn2 D38117 97942_g_at −1.560.00 0.00 6.16 40.88 8.57 CAPN6 Y12582 97941_at 0.00 0.00 0.00 0.00 8.692.20 CAPN6 Y12582 97943_at 0.00 0.00 0.00 1.98 4.94 2.50 CAPN6 AI74713393499_at 0.00 3.32 1.92 3.16 4.17 4.70 capping protein U16740 alpha 1;Cappa1 102248_f_at 0.00 1.87 0.00 2.83 3.31 2.91 CASK Y17138 102064_at0.00 1.72 0.00 2.05 1.38 2.48 CASP1 L28095 99049_at 0.00 0.00 0.00 0.002.36 3.08 caspase 2; Casp2 D28492 98436_s_at 0.00 0.00 2.32 3.29 4.633.72 apoptosis related U54803 cysteine protease; Casp3 94458_at 0.000.00 0.00 0.00 3.24 3.31 CASP6 Y13087 102328_at 1.67 0.00 3.82 0.00 5.014.40 CASP8 AJ007749 93364_at 0.00 1.84 0.00 2.26 2.32 2.91 CATNA1 X5999098151_s_at 0.00 0.00 0.00 0.00 1.80 3.29 catenin src; Catns Z1780494817_at 0.00 2.19 2.44 4.38 4.24 4.34 CBP1 X60676 93697_at 0.00 0.000.00 0.00 1.72 3.53 CBX4 U63387 99186_at 0.00 8.48 3.62 3.94 5.08 3.50CCNA2 X75483 94294_at 0.00 2.93 3.54 5.89 5.22 5.58 cyclin B2; Ccnb2X66032 94232_at 0.00 2.12 1.47 1.84 2.61 2.72 CCND1 AI849928 99535_at2.08 1.94 0.00 0.00 0.00 0.00 CCR4 AW047630 98153_at 0.00 0.00 0.00 2.041.83 0.00 chaperonin subunit 3 L20509 (gamma); Cct3 98446_s_at 0.00 1.831.75 2.36 1.70 0.00 EPHB4 U06834 98088_at 0.00 0.00 1.54 0.00 2.87 0.00CD14 antigen; Cd14 X13333 103422_at 0.00 0.00 0.00 0.00 2.42 7.86 Cd1d1M63695 101897_g_at 0.00 0.00 0.00 0.00 2.31 5.91 Cd1d2 M63697103005_s_at 2.64 4.50 2.70 3.84 3.12 5.15 CD44 X66084 114697_at 2.654.08 3.95 6.25 8.24 22.18 CD44 AI594062 103089_at 0.00 4.30 5.56 6.225.21 4.03 CD48 antigen; Cd48 X53526 104606_at 2.11 3.68 3.52 4.72 4.147.46 CD52 antigen; Cd52 M55561 94939_at 2.23 3.23 3.49 4.50 3.47 5.59CD53 antigen; Cd53 X97227 103016_s_at 0.00 2.52 3.48 6.07 4.53 15.71CD68 X68273 101878_at 0.00 2.02 3.26 3.66 4.16 3.58 CD72 antigen; Cd72J04170 99584_at 0.00 2.17 0.00 3.40 2.84 2.83 CD82 antigen; Cd82 D14883103040_at 0.00 0.00 0.00 0.00 1.56 2.15 CD83 AI837100 95661_at 0.00 0.000.00 0.00 1.33 2.18 CD9 L08115 102934_s_at 0.00 1.60 0.00 2.80 2.37 0.00CDC25C L16926 100128_at 0.00 8.81 12.87 15.86 16.72 6.21 CDC2A M38724103821_at 0.00 1.77 1.70 1.97 2.01 0.00 CDC6 AJ223087 100006_at 0.000.00 0.00 0.00 6.64 5.01 CDH11 D21253 102852_at 0.00 0.00 0.00 0.00 7.689.75 cadherin 2; Cdh2 M31131 94412_at 0.00 0.00 0.00 0.00 2.88 3.60 CDK2AJ223733 101017_at 0.00 0.00 0.00 0.00 3.17 2.52 CDK4 AA791962 100444_at0.00 0.00 0.00 0.00 3.47 0.00 cyclin-dependent D29678 kinase 5; Cdk594881_at 0.00 0.00 0.00 0.00 3.11 0.00 CDKN1A AW048937 98067_at 0.000.00 0.00 0.00 5.18 0.00 cyclin-dependent U09507 kinase inhibitor 1A(P21); Cdkn1a 95471_at 0.00 −2.68 −2.76 0.00 2.10 1.92 cyclin-dependentU22399 kinase inhibitor 1C (P57); Cdkn1c 101900_at 0.00 0.00 0.00 0.006.10 1.30 CDKN2B AF059567 93094_at 0.00 0.00 0.00 0.00 3.46 3.26degeneration-related U88588 2; Cdr2 109137_at 0.00 0.00 0.00 0.00 3.393.25 CDYL AI157065 100616_at 0.00 0.00 0.00 0.00 2.44 0.00 CENPAAF012710 98770_at 0.00 0.00 0.00 0.00 2.24 0.00 CENPC AF012708107597_f_at 0.00 0.00 4.29 2.70 3.37 0.00 UNK_AA637016 AA63701692788_f_at 0.00 0.00 0.00 2.36 2.67 2.72 CETN3 Y12474 93784_at 0.00 0.000.00 2.99 3.88 2.71 CFDP AB010828 101853_f_at 0.00 0.00 0.00 0.00 3.4211.91 component factor h; M12660 Cfh 92291_f_at 0.00 0.00 0.00 0.00 3.0513.62 related protein; M29008 CFHRB 99119_at 0.00 2.89 3.39 4.99 6.156.26 cofilin 1, non- D00472 muscle; Cfl1 99120_f_at 0.00 0.00 0.00 2.062.24 1.88 cofilin 1 , non- R75450 muscle; Cfl1 104509_at 0.00 1.89 0.000.00 2.34 0.00 CH25H-PENDING AF059213 101459_at 0.00 0.00 0.00 0.00 1.602.02 helicase DNA L10410 binding protein 1; Chd1 103088_at 0.00 3.212.88 0.00 0.00 0.00 close homolog of L1; X94310 Chl1 100021_at 0.00 0.002.97 7.77 7.91 0.00 ACRA M17640 96549_at 0.00 0.00 0.00 0.00 3.62 0.00acetylcholine L10076 receptor delta; Acrd 102639_at 0.00 0.00 1.92 2.412.72 2.04 CHTS2 AB011451 92832_at 0.00 0.00 0.00 0.00 4.30 0.00 CISH1U88325 92232_at 6.68 28.29 0.00 13.77 17.42 5.49 cytokine inducibleU88328 SH2-containing protein 3; Cish3 93126_at 0.00 0.00 0.00 0.00 2.5710.46 creatine kinase, X04591 brain; Ckb 97468_at 0.00 6.71 10.12 11.3113.78 6.31 CKS1 AB025409 92762_at 2.53 6.19 4.80 3.95 2.46 3.99 CLECSF6AJ133533 94256_at 0.00 2.07 2.20 3.05 4.36 3.47 CLIC4 AI849533 94254_at0.00 0.00 1.62 2.70 2.24 3.40 CLIC4 AI845237 94255_g_at 0.00 1.55 1.902.51 1.93 3.71 CLIC4 AI845237 103346_at 0.00 0.00 0.00 0.00 2.31 2.73CLK2 AF033564 100579_s_at 0.00 2.13 2.05 2.61 2.89 3.28 polypeptide(Lca); U91848 Clta 95286_at 0.00 1.77 0.00 2.24 0.00 0.00 CLU D14077102794_at 0.00 0.00 1.89 2.10 1.38 1.53 CMKAR4 Z80112 93397_at 2.34 4.183.03 4.05 2.45 3.21 chemokine (C—C) U56819 receptor 2; Cmkbr2 102718_at2.24 3.99 3.37 0.00 2.71 0.00 CMKBR5 AF022990 102719_f_at 1.75 3.77 2.232.28 2.38 1.33 chemokine (C—C) X94151 receptor 5; Cmkbr5 94004_at 0.000.00 0.00 3.43 10.86 9.73 calponin 2; Cnn2 Z19543 100481_at 0.00 0.000.00 0.00 20.07 11.26 procollagen. type XI, D38162 alpha 1;Col11a1103616_at 0.00 0.00 0.00 0.00 25.14 34.25 UNK_AF100956 AF100956 92314_at0.00 0.00 0.00 0.00 10.67 0.00 XII, alpha 1; U25652 Col12a1 102261_f_at0.00 0.00 0.00 0.00 2.65 4.65 COL13A1 U30292 102262_r_at 0.00 0.00 0.000.00 4.29 6.76 COL13A1 U30292 99476_at 0.00 0.00 0.00 1.84 2.80 2.91COL14A1 AJ131395 99637_at 0.00 0.00 0.00 2.41 2.14 2.67 srocollagen,type AF011450 XV; Col15a1 99638_at 0.00 0.00 0.00 3.24 5.40 5.62procollagen, type D17546 XV; Col15a1 101881_g_at 0.00 0.00 0.00 4.8110.82 10.32 COL18A1 L22545 102990_at 0.00 2.15 3.36 6.99 10.03 12.96COL3A1 AA655199 98331_at 0.00 0.00 0.00 2.60 3.93 4.38 procollagen, typeIII, X52046 alpha 1; Col3a1 101093_at 0.00 0.00 0.00 2.28 2.02 2.23COL4A1 M15832 101080_at 0.00 1.80 3.49 9.91 19.47 13.93 COL5A1 AB009993101906_at 0.00 2.48 3.11 5.07 3.93 3.93 COL5A2 AA032310 92567_at 0.001.92 2.95 6.03 7.55 9.22 procollagen, type V, L02918 alpha 2; Col5a2113235_at 0.00 0.00 0.00 2.96 1.95 3.12 COL5A3 AA734782 95493_at 0.000.00 0.00 3.72 3.84 3.50 procollagen, type VI, X66405 alpha 1; Col6a193517_at 0.00 0.00 1.99 4.43 6.38 5.80 COL6A2 Z18272 101110_at 0.00 0.002.32 5.51 6.14 5.80 COL6A3 AF064749 100308_at 0.00 2.74 2.14 6.75 37.3514.46 procollagen, type X66976 VIII, alpha 1; Col8a1 104483_at 0.00 0.000.00 0.00 32.61 0.00 COL9A1 L12215 98027_at 0.00 0.00 0.00 0.00 4.610.00 procollagen, type IX, Z22923 alpha 2; Col9a2 102070_at 0.00 0.000.00 0.00 13.24 0.00 UNK_AW212495 AW212495 94305_at 0.00 0.00 0.00 2.820.00 0.00 COLA1 U03419 93340_f_at 0.00 0.00 0.00 4.50 3.30 2.24 COPB2AF043120 93341_r_at 0.00 0.00 0.00 2.46 2.84 1.83 COPB2 AF04312098930_at 0.00 0.00 0.00 0.00 2.06 0.00 UNK_AI844701 AI844701 110860_at0.00 0.00 3.09 3.85 1.24 3.46 COPEB AI846501 94427_at 0.00 0.00 0.002.68 4.76 3.81 COPG1 AI841737 96936_at 0.00 0.00 0.00 2.28 4.10 2.32COPG1 AI020792 95149_at 0.00 0.00 0.00 2.58 1.86 2.06 UNK_AW121088AW121088 104143_at 0.00 0.00 0.00 2.36 3.59 3.04 UNK_AI843212 AI84321296648_at 0.00 13.50 4.26 0.00 5.51 6.88 CORO1A AW122039 98928_at 0.001.68 0.00 3.37 5.06 5.56 CORO1B AW122820 99631_f_at 0.00 1.54 0.00 2.842.08 3.07 COX6A1 U08440 92851_at 0.00 0.00 0.00 0.00 2.49 8.74ceruloplasmin; Cp U49430 95514_at 0.00 0.00 0.00 2.96 4.71 2.89UNK_AI846302 AI846302 93320_at 0.00 1.78 2.64 3.70 2.65 3.94 camitineAF017175 palmitoyltransferase 1, liver; Cpt1a 103492_at 0.00 0.00 0.000.00 10.90 5.75 UNK_AF077738 AF077738 98415_at 0.00 0.00 0.00 0.00 1.352.34 CREME9-PENDING AF046060 98395_at 2.46 1.94 0.00 0.00 0.00 0.00CRHR2 U21729 94061_at 0.00 0.00 0.00 2.64 1.93 2.29 intestinal protein;M13018 Crip 101879_s_at 0.00 0.00 0.00 0.00 1.75 2.34 CRRY M23529103817_at 0.00 2.19 2.37 5.07 8.57 7.80 UNK_AJ006469 AJ006469 92506_at0.00 0.00 0.00 0.00 8.84 0.00 CRTL1 AF098460 101450_at 2.70 2.74 0.000.00 2.07 3.42 factor 1 M21952 (macrophage); Csf1 104354_at 0.00 2.653.08 4.25 2.85 6.88 factor 1 receptor; X06368 Csf1r 99330_at 0.00 2.372.21 3.33 2.11 4.32 factor 2 receptor, M85078 alpha, low-affinity(granulocyte- macrophage); 94284_at 0.00 0.00 0.39 3.31 2.27 2.13UNK_AW122731 AW122731 103210_at 0.00 0.00 0.00 2.89 1.78 2.62 factor 2receptor, M29855 beta 2, low-affinity (granulocyte- macrophage);104248_at 0.00 0.00 0.00 2.35 2.26 2.03 CSNK AW227650 104249_g_at 0.000.00 0.00 1.76 2.15 1.71 CSNK AW227650 100019_at 6.42 11.38 13.27 12.7512.15 9.66 proteoglycan 2; D45889 Cspg2 92608_at 0.00 0.00 2.71 4.255.49 2.97 cysteine rich protein; D88793 Csrp 93550_at 0.00 2.70 4.7012.96 26.37 8.78 cysteine-rich protein D88792 2; Csrp2 100581_at 0.001.94 2.02 3.94 2.84 7.19 cystatin B; Cstb U59807 92554_at 0.00 0.00 0.001.95 2.32 2.05 CTBP2 AF059735 100148_at 0.00 0.00 0.00 0.00 2.25 0.00CCCTC-binding U51037 factor; Ctcf 96912_s_at 0.00 2.20 1.97 3.68 2.784.45 lymphocyte- X15591 associated protein 2 alpha; Ctla2a 103518_at0.00 3.44 3.65 4.74 0.00 0.00 lymphocyte- X15592 associated protein 2beta; Ctla2b 103341_at 0.00 1.78 2.25 2.07 1.92 0.00 triphosphate U49350synthase; Ctps 101019_at 2.09 3.57 4.51 4.05 2.09 2.70 CTSC U74683101020_at 0.00 3.36 5.06 4.28 2.46 3.04 CTSC AI842667 94834_at 0.00 1.762.32 4.76 5.57 5.93 cathepsin H; Ctsh U06119 98543_at 0.00 1.80 2.383.24 2.52 4.10 CTSS AJ223208 92633_at 0.00 1.52 2.44 2.98 2.97 6.50D2WSU143E AJ242663 94054_at 0.00 0.00 0.00 2.97 4.15 3.29 CTTN AI84180894055_at 0.00 0.00 2.52 0.00 5.91 4.16 cortactin; Cttn U03184 97013_f_at0.00 2.71 3.17 4.89 4.48 5.87 CYBA AW046124 100059_at 0.00 2.19 2.493.52 3.30 4.51 alpha polypeptide; M31775 Cyba 100300_at 0.00 0.00 1.712.50 2.50 3.11 beta polypeptide; U43384 Cybb 99979_at 1.51 4.39 2.855.07 6.42 9.91 CYP1B1 X78445 94916_at 0.00 1.59 0.00 2.47 2.67 0.00UNK_AW122260 AW122260 92777_at 0.00 2.49 3.85 4.95 3.04 1.84 cysteinerich protein M32490 61; Cyr61 98619_at 0.00 0.00 0.00 0.00 3.27 0.00UNK_AW121709 AW121709 106255_at 0.00 2.41 2.03 4.64 4.43 4.94UNK_AI840993 AI840993 104358_at 0.00 0.00 0.00 1.86 5.05 0.00UNK_AI853668 AI853668 107526_at 0.00 0.00 0.00 0.00 1.84 2.42UNK_AA710084 AA710084 111683_at 0.00 0.00 0.00 2.21 2.79 4.85 D10UCLA1AA153345 112407_at 0.00 0.00 0.00 0.00 2.20 3.03 D10UCLA1 AI02147097824_at 0.00 1.87 2.19 2.60 2.50 1.64 UNK_AW121031 AW121031 94339_at0.00 0.00 0.00 0.00 2.33 1.99 UNK_AI841330 AI841330 94242_at 0.00 0.000.00 2.16 1.70 1.68 UNK_AA881309 AA881309 93427_at 0.00 0.00 0.00 2.346.05 11.04 UNK_AW122310 AW122310 95480_at 0.00 0.00 0.00 0.00 2.18 0.00D11WSU68E AI847163 107600_at 0.00 0.00 0.00 1.79 2.58 0.00 UNK_AI838753AI838753 111518_at 0.00 0.00 0.00 0.00 2.20 3.30 UNK_AA170647 AA17064793775_at 0.00 0.00 0.00 1.81 1.83 2.23 UNK_AI841894 AI841894 98061_at0.00 0.00 0.00 0.00 3.19 2.83 UNK_AI841192 AI841192 104558_at 0.00 0.000.00 0.00 4.22 3.13 D12WSU95E AA867123 101372_at 0.00 0.00 0.00 2.812.01 0.00 UNK_AI852645 AI852645 98918_at 0.00 0.00 0.00 4.35 5.87 3.22D13WSU115E AI841920 94452_g_at 0.00 0.00 1.63 2.11 2.04 0.00 D13WSU123EAI787627 94450_at 0.00 0.00 1.73 2.44 0.00 0.00 D13WSU123E AI85420294502_at 0.00 1.78 0.00 4.75 3.35 3.47 D13WSU50E AW125724 104419_at 0.001.94 0.00 0.00 2.42 3.99 UNK_AI132380 AI132380 97325_at 0.00 0.00 0.002.68 2.67 2.97 UNK_AA881294 AA881294 94561_at 0.00 0.00 0.00 3.23 4.123.13 UNK_AI836140 AI836140 110414_at 0.00 0.00 0.00 2.05 5.26 3.81UNK_AI594455 AI594455 111499_at 0.00 0.00 0.00 1.56 1.93 2.42UNK_AW046236 AW046236 98013_at 0.00 1.88 2.52 0.00 3.28 3.54UNK_AA666464 AA666464 114305_at 0.00 0.00 0.00 0.00 4.13 5.18UNK_AA739238 AA739238 104633_at 0.00 4.17 3.44 3.82 3.73 2.71 D15WSU122EAW123921 97822_at 0.00 0.00 0.00 0.00 3.38 2.85 UNK_AW122689 AW12268997821_at 0.00 0.00 0.00 2.99 0.00 0.00 UNK_AI646056 AI646056 97823_g_at0.00 0.00 0.00 0.00 1.81 2.08 UNK_AW122689 AW122689 95063_at 0.00 0.000.00 2.11 2.59 1.68 UNK_AI606257 AI606257 95137_at 0.00 3.19 3.65 7.6911.28 4.71 UNK_AI852985 AI852985 97921_at 0.00 0.00 0.00 0.00 2.36 0.00UNK_AI846279 AI846279 110388_at 0.00 0.00 0.00 0.00 2.12 0.00UNK_AW213204 AW213204 115074_at 0.00 2.62 2.33 3.85 12.14 4.46UNK_AI197311 AI197311 111433_at 0.00 0.00 0.00 2.83 5.30 0.00UNK_AA795610 AA795610 109692_at 0.00 0.00 2.28 1.49 0.00 0.00UNK_AI848006 AI848006 104333_at 0.00 6.18 7.27 7.18 9.71 6.35 DMAsegment, Chr U69488 17, human D6S56E 5; D17H6S56E-5 96318_at 0.00 0.000.00 3.10 4.21 3.13 D17WSU104E AW045739 134595_at 0.00 0.00 0.00 2.882.15 2.49 UNK_AI006117 AI006117 100154_at 0.00 0.00 0.00 2.77 1.72 2.56D17WSU91E AI836367 104090_at 0.00 0.00 0.00 0.00 2.38 2.01 UNK_AA657164AA657164 96346_at 0.00 −1.46 −2.12 0.00 2.45 5.93 D18UCLA3 AI85402094967_at 0.00 0.00 0.00 0.00 1.66 3.20 UNK_AI851365 AI851365 96838_at0.00 0.00 0.00 0.00 4.46 0.00 RCE1 AI851223 107005_at 0.00 0.00 0.001.90 3.19 0.00 UNK_AI853916 AI853916 113182_at 0.00 0.00 0.00 1.92 2.430.00 UNK_AI844871 AI844871 112787_f_at 0.00 0.00 0.00 2.64 2.54 2.82UNK_AI838572 AI838572 112786_i_at 0.00 0.00 0.00 4.53 3.47 0.00UNK_AI838572 AI838572 103310_at 0.00 0.00 0.00 0.00 2.12 1.91 0 AA220427104740_at 0.00 0.00 0.00 0.00 2.41 2.78 UNK_AW125318 AW125318 95428_at0.00 0.00 2.83 0.00 1.99 0.00 D1WSU40E AA688761 104602_at 0.00 1.59 0.000.00 1.70 3.29 UNK_AW121972 AW121972 104640_f_at 0.00 0.00 0.00 2.442.40 2.19 UNK_AI464596 AI464596 104639_i_at 0.00 0.00 0.00 2.93 2.830.00 UNK__AI464596 AI464596 104225_at 0.00 0.00 0.00 0.00 2.10 2.21UNK_AI645050 AI645050 100054_s_at 0.00 0.00 0.00 0.00 2.09 0.00 ENDOGAW123127 107513_at 0.00 0.00 0.00 2.31 3.11 2.79 UNK_AW123087 AW12308795708_at 0.00 2.11 3.22 5.70 7.02 8.87 UNK_AI843466 AI843466 98016_at0.00 0.00 0.00 2.43 0.00 0.00 D3WSU161E AA981268 95477_at 0.00 0.00 0.000.00 2.08 2.36 UNK_AW125185 AW125185 99621_s_at 0.00 2.08 2.54 2.56 2.882.85 splicing factor AA690583 proline/glutamine rich (polypyrimidinetract-binding protein- associated) (human) 97295_at 0.00 2.47 4.02 4.103.48 2.80 UNK_AW122331 AW122331 104116_at 2.55 2.60 2.64 1.68 0.00 0.00UNK_AW124049 AW124049 107574_at 0.00 0.00 0.00 2.45 2.15 3.00UNK_AI836723 AI836723 98092_at 3.04 3.06 5.10 7.71 4.52 10.69 D5WSU111EAA790307 104176_at 0.00 0.00 0.00 0.00 4.07 3.97 UNK_AI850941 AI85094196675_at 0.00 0.00 0.00 1.94 2.68 2.48 UNK_AW124245 AW124245 104168_at0.00 2.74 2.34 3.99 2.65 3.50 UNK_AA791742 AA791742 94237_at 0.00 2.353.47 5.76 4.82 3.95 D6WSU137E AI846708 95541_at 0.00 2.27 0.00 4.67 5.625.12 D6WSU176E AW125506 104300_at 0.00 1.95 2.90 6.09 4.75 5.14 IQGAP1AI117936 95032_at 0.00 3.40 3.29 6.75 7.34 1.97 PRC1 AA856349 103871_at0.00 0.00 0.00 3.06 3.70 1.44 UNK_AW123729 AW123729 110005_at 0.00 1.940.00 3.25 7.31 5.69 UNK_AA839741 AA839741 103862_r_at 0.00 0.00 0.002.45 2.02 2.13 D7WSU128E AA388099 103861_s_at 0.00 0.00 0.00 2.07 2.290.00 D7WSU128E AA388099 95709_at 0.00 0.00 0.00 3.89 6.25 6.07 D7WSU86EAW012491 106634_at 0.00 0.00 0.00 2.10 0.00 0.00 UNK_AW123293 AW12329396325_at 0.00 0.00 0.00 0.00 1.66 2.12 D8WSU108E AW124874 95430_f_at0.00 1.77 0.00 2.65 2.71 3.32 D9WSU18E AI854154 98045_s_at 2.72 5.833.95 5.13 4.15 3.08 disabled homolog 2 U18869 (Drosophila); Dab298044_at 1.21 2.07 0.00 0.00 1.74 0.00 disabled homolog 2 U18869(Drosophila); Dab2 96008_at 0.00 0.00 0.00 1.99 2.36 0.00 DAD1 U81052117012_g_at 0.00 0.00 0.00 4.00 7.90 3.56 UNK_AW105743 AW105743117011_at 0.00 0.00 0.00 0.00 3.01 0.00 UNK_AW105743 AW105743 103430_at0.00 0.00 0.00 0.00 2.05 0.00 UNK_AW124952 AW124952 95529_at 0.00 1.862.09 5.10 2.54 3.94 drebrin-like; Dbnl U58884 98071_f_at 0.00 2.00 3.673.69 3.07 3.72 deoxycytidine X77731 kinase; Dck 101104_at 0.00 0.00 0.001.46 1.46 2.07 critical region gene AB001990 a; Dcra 96636_at 0.00 1.431.65 2.07 1.84 1.97 UNK_AI852649 AI852649 95682_at 0.00 0.00 0.00 2.052.47 1.54 DDB1 AB026432 95683_g_at 0.00 0.00 0.00 1.88 2.50 1.80 DDB1AB026432 100513_at 0.00 0.00 0.00 1.68 4.36 3.45 DDEF1 AF075461101074_at 0.00 0.00 2.79 4.38 3.63 2.36 phosphooligosaccha D89063ride-protein glycotransferase; Ddost 103598_at 0.00 1.59 0.00 3.29 2.242.18 DDX9 U91922 131478_at 0.00 0.00 0.00 0.00 3.96 3.79 DECR2 AW12065495688_at 0.00 1.75 1.72 2.39 2.05 2.52 spermatocyte Y08460 homolog(Drosophila); Degs 93188_at 0.00 0.00 0.00 4.20 11.48 5.36 DKK3 AJ243964102207_at 0.00 0.00 0.00 0.00 3.35 3.26 UNK_AW123249 AW123249 101975_at0.00 0.00 0.00 0.00 1.62 3.17 DLK1 Z12171 92332_at 0.00 0.00 2.88 0.002.22 0.00 distal-less M80540 homeobox 2; Dlx2 92930_at 0.00 0.00 0.000.00 8.22 7.47 distal-less U67840 homeobox 5; Dlx5 96703_at 0.00 1.793.01 7.33 9.33 5.98 UNK_AB029448 AB029448 103344_at 0.00 0.00 0.00 0.002.04 2.64 DnaJ-like protein 1; L16953 Dnajl1 99184_at 0.00 0.00 0.000.00 1.89 2.60 DNASE2 AW120896 96298_f_at 0.00 1.82 1.92 3.10 3.96 3.65UNK_AF020185 AF020185 103030_at 0.00 0.00 0.00 4.57 7.87 4.91 dynamin;Dnm L31397 103031_g_at 0.00 0.00 0.00 0.00 3.09 3.12 dynamin; Dnm L31397101445_at 0.00 2.65 0.00 0.00 0.00 0.00 DNMT AF036008 113211_at 0.000.00 3.68 4.25 6.78 3.64 DNT-PENDING AW049974 102896_at 0.00 0.00 2.043.64 4.81 3.43 tyrosine kinase 1; U78818 Dok1 102334_at 3.08 3.91 0.000.00 0.00 0.00 DOK2 AF059583 101503_at 3.58 3.12 4.04 8.95 7.81 5.99dihydropyrimidinase- X87817 like 3; Dpysl3 102374_at 0.00 0.00 0.00 0.004.74 4.92 DSCR1L2 AI847661 97341_at 0.00 2.40 3.13 6.07 15.30 4.95DXIMX39E AW124082 96813_f_at 0.00 0.00 1.72 2.21 1.85 2.48 DXIMX46EAI852973 112941_f_at 0.00 1.46 2.93 3.92 4.37 4.97 UNK_AA960514 AA960514112940_i_at 0.00 0.00 0.00 2.74 5.32 7.05 UNK_AA960514 AA960514115503_at 0.00 0.00 0.00 2.37 0.00 0.00 UNK_AI536452 AI536452 93306_at0.00 1.46 0.00 2.07 1.87 1.74 polyposis coli U51196 binding protein Eb1;Eb1 96627_at 0.00 2.70 0.00 4.71 4.42 3.78 Ca2+ antagonist X97755(emopamil) binding protein; Ebp 97411_at 0.00 2.04 3.41 2.85 4.03 1.78ect2 oncogene; Ect2 L11316 92352_at 0.00 0.00 0.00 0.00 2.00 3.30 EDG3AF108021 92867_at 0.00 0.00 0.00 0.00 4.47 3.82 EDR2 AF060076 113230_at0.00 12.60 18.55 27.29 46.06 32.08 UNK_AW210333 AW210333 98407_at 0.000.00 0.00 0.00 4.30 3.00 ephrin B1; Efhb1 U07602 96195_at 0.00 0.00 0.000.00 2.74 5.31 embryonal Fyn- U57686 associated substrate; Efs101842_g_at 0.00 0.00 0.00 0.00 2.82 0.00 EGFR AW049716 115396_at 0.000.00 0.00 0.00 4.40 0.00 UNK_AW212285 AW212285 93058_at 0.00 2.41 2.494.00 4.26 3.39 UNK_AF026481 AF026481 103537_at 0.00 1.28 0.00 0.00 1.952.34 EIF2AK3 AF076681 99101_at 0.00 0.00 0.00 2.72 2.29 0.00 EIF3S7AB012580 92816_r_at 0.00 1.75 1.97 0.00 2.95 2.45 EIF4A1 X03039 93783_at0.00 0.00 0.00 0.00 2.98 0.00 0 M27347 99984_at 0.00 0.00 0.00 0.00 2.332.51 ELK3 L19953 101560_at 2.84 8.50 10.71 11.39 7.26 13.98 EMB AW06133097426_at 0.00 1.52 2.41 2.31 3.42 2.86 EMP1 X98471 93593_f_at 2.04 3.043.13 4.60 5.82 4.88 EMP3 U87948 103507_at 0.00 4.51 20.15 12.03 5.176.40 containing, mucin- X93328 like, hormone receptor-like sequence 1;Emr1 100134_at 0.00 0.00 0.00 4.01 4.92 4.32 endoglin; Eng X77952106642_at 0.00 0.00 1.68 0.00 3.70 1.79 UNK_AW260744 AW260744 104174_at0.00 0.00 0.00 5.50 8.69 10.09 phosphodiesterase J02700 I/nucleotidepyrophosphatase 1; Pdnp1 115369_at 0.00 0.00 2.74 4.43 7.92 3.04EPB4.1L3 AI835976 96623_at 0.00 2.54 2.75 4.70 5.02 3.50 EPCS21-PENDINGAI853172 103980_at 0.00 0.00 0.00 0.00 4.49 0.00 Epha2 U07634 95298_at0.00 0.00 0.00 0.00 3.47 1.35 Epha3 M68513 93469_at 0.00 0.00 0.00 0.006.34 0.00 EPHB3 Z49086 104482_at 0.00 0.00 0.00 0.00 6.75 0.00epimorphin; Epim D10475 98992_at 0.00 0.00 0.00 2.10 3.71 0.00EPPB9-PENDING AB030483 104006_at 0.00 2.64 0.00 0.00 0.00 0.00 factorreceptor L21768 pathway substrate 15; Eps15 93670_at 0.00 0.00 0.00 4.024.90 3.90 ERF AW048233 94040_at 0.00 1.72 0.00 2.76 2.29 1.74rudimentary D73368 homolog (Drosophila); Erh 98129_at 0.00 1.68 0.004.36 7.07 5.75 UNK_AI852553 AI852553 113283_at 0.00 0.00 2.92 3.42 2.284.63 ESTM25 AI036047 113563_at 0.00 0.00 0.00 0.00 2.14 2.15 ESTM3AI845154 100348_at 0.00 0.00 3.31 0.00 3.48 2.28 ESTM4 AW214136 98025_at1.99 3.06 3.68 5.90 5.31 4.61 integration site 2; M34896 Evi2 98026_g_at0.00 2.64 3.50 4.48 4.34 4.88 integration site 2; M34896 Evi2 94810_at0.00 1.61 0.00 2.32 2.75 2.25 Ewing sarcoma X79233 homolog; Ewsh102811_at 0.00 1.49 2.88 2.92 4.07 10.13 exostoses (multiple) X96639 1;Ext1 141160_f_at 0.00 0.00 0.00 10.92 7.94 16.18 EXT1 AA710704 99929_at0.00 0.00 0.00 0.00 2.47 2.05 EXT2 U72141 99917_at 0.00 0.00 2.33 2.282.10 0.00 enhancer of zeste U52951 homolog 2 (Drosophila); Ezh2 95313_at0.00 0.00 0.00 0.00 2.80 5.33 UNK_AW046032 AW046032 98967_at 0.00 6.617.73 7.50 4.13 2.08 protein 7, brain; U04827 Fabp7 98588_at 0.00 0.000.00 2.92 5.68 4.75 FAH Z11774 92441_at 0.00 0.00 0.00 1.93 5.31 12.02FAP Y10007 96119_s_at 0.00 0.00 0.00 0.00 3.68 4.93 UNK_AA797604AA797604 102114_f_at 0.00 0.00 0.00 0.00 3.74 7.50 UNK_AI326963 AI32696394309_g_at 0.00 0.00 0.00 0.00 1.66 2.46 fibulin 1; Fbln1 X70853101090_at 0.00 1.63 0.00 3.44 2.92 3.24 fibrillin 1; Fbn1 L29454103623_at 0.00 0.00 0.00 −0.04 3.50 0.00 fibrillin 2; Fbn2 L39790130689_at 0.00 1.99 0.00 4.20 3.52 0.00 FBXO17 AI957104 102879_s_at 2.152.81 3.04 3.28 2.15 0.00 Fc receptor, IgG, M31314 high affinity I; Fcgr1101793_at 9.28 18.31 11.96 6.48 1.72 0.00 FCGR1 X70980 102337_s_at 0.006.07 3.61 4.74 4.61 2.61 FCGR2B M31312 97327_at 0.00 2.17 3.19 3.45 1.910.00 specific L26320 endonuclease 1; 92188_s_at 0.00 0.00 0.00 1.71 2.162.22 feline sarcoma X12616 oncogene; Fes 93674_at 0.00 0.00 0.00 2.363.64 0.00 dysplasia homolog; U22325 Fgd1 115755_g_at 0.00 0.00 2.87 3.030.00 0.00 FGD2 AA958624 97509_f_at 0.00 0.00 0.00 0.00 2.00 2.61 FGFR1U22324 93090_at 0.00 2.25 0.00 0.00 15.83 12.11 FGFR2 M23362 93091_s_at0.00 0.00 0.00 0.00 12.79 8.09 factor receptor 2; M63503 Fgfr2 100884_at0.00 8.62 5.24 11.29 12.67 10.44 factor regulated U04204 protein; Fgfrp108539_at 1.30 2.97 3.41 3.92 1.57 0.00 FGFRP2-PENDING AI853558100986_at 0.00 0.00 0.00 1.61 2.26 2.55 FHL2 AF055889 99176_at 0.00 0.000.00 0.00 2.80 2.04 UNK_AI843393 AI843393 97421_at 0.00 3.18 3.75 4.375.50 2.59 factor inducible 16; U42385 Fin16 93294_at 6.49 4.31 6.60 6.529.13 4.84 secreted protein; M70642 Fisp12 103248_at 0.00 0.00 0.00 0.004.54 0.00 FKBP1B AF060872 99546_at 0.00 2.31 0.00 3.07 2.84 2.41 protein2 (13 kDa); M77831 Fkbp2 99082_at 0.00 2.02 2.88 8.30 16.01 13.94protein 6 (65 kDa); L07063 Fkbp6 104746_at 0.00 0.00 0.00 4.08 8.21 6.92FKBP7 AF040252 93731_at 0.00 0.00 0.00 2.75 3.90 3.42 FKBP9 AF09033498441_at 0.00 2.19 2.46 3.50 3.23 2.83 retardation L23971 syndrome 1homolog; Fmr1 104172_at 0.00 1.74 2.18 2.78 1.72 0.00 folate bindingprotein M64817 2; Folbp2 92838_at 0.00 0.00 0.00 0.00 2.65 0.00 FSCN1L33726 98817_at 0.00 2.64 0.00 0.00 4.80 0.00 follistatin; Fst Z29532105369_at 0.00 0.00 2.20 2.45 3.39 3.07 UNK_AW123943 AW123943 94833_at0.00 1.28 0.00 3.60 2.58 3.49 follistatin-like; Fstl M91380 103394_at1.84 3.58 3.01 6.10 4.57 16.04 containing ion U72680 transport regulator5; Fxyd5 100133_at 0.00 0.00 0.00 2.50 2.89 3.88 FYN M27266 93681_at0.00 0.00 0.00 5.25 7.24 0.00 UNK_AW123618 AW123618 97531_at 0.00 0.000.00 15.58 0.00 0.00 G0/G1 switch gene X95280 2; G0s2 97516_at 0.00 2.182.47 4.38 4.79 5.05 alpha glucosidase 2, U92793 alpha neutral subunit;G2an 101294_g_at 0.00 3.52 2.38 0.00 1.94 3.20 G6PD2 Z84471 102292_at2.03 2.13 1.47 0.00 0.00 0.00 DDIT1 U00937 101979_at 2.21 2.10 0.00 2.232.97 0.00 GADD45G AF055638 109336_at 0.00 0.00 0.00 0.00 3.83 0.00GADD45G AI035425 103367_at 0.00 2.04 0.00 0.00 2.18 2.73UDP-N-acetyl-alpha- U18975 D-galactosamine: (N- acetylneuraminyl)-galactosylglucosyl- ceramide-beta-1, 4-N- acetylgalactosaminyltransferase; Galgt1 115517_at 0.00 1.62 0.00 0.00 3.39 3.09 GALNSAI845504 94338_g_at 0.00 0.00 0.00 0.00 2.27 0.00 growth arrest M21828specific 2; Gas2 98530_at 0.00 0.00 0.00 0.00 3.47 2.41 GAS5 AI84961598531_g_at 0.00 0.00 0.00 2.10 2.16 1.73 GAS5 AI849615 99067_at 0.001.65 1.75 2.27 2.93 2.61 growth arrest X59846 specific 6; Gas6 100488_at0.00 0.00 0.00 2.15 2.08 2.54 acid beta M24119 glucosidase; Gba103202_at 0.00 0.00 3.29 4.08 1.83 3.84 GBP3 AW047476 114351_at 0.000.00 0.00 1.71 2.75 4.42 GCL AA727943 92655_at 0.00 0.00 0.00 2.20 1.930.00 glucosaminyl (N- U19265 acetyl) transferase 1, core 2; Gcnt1109332_at 0.00 0.00 0.00 1.55 2.61 0.00 UNK_AW046226 AW046226 103590_at0.00 0.00 0.00 2.29 5.83 3.68 UNK_AI507104 AI507104 93575_at 0.00 0.000.00 0.00 2.41 3.91 GGH AF051102 102993_at 0.00 0.00 0.00 3.30 3.20 2.75glycoprotein M85153 galactosyltransferase alpha 1, 3; Ggta1 100064_f_at0.00 2.51 1.94 4.11 5.60 7.77 GJA1 M63801 100065_r_at 0.00 2.36 1.963.86 7.28 15.07 GJA1 M63801 104016_at 0.00 2.45 0.00 0.00 0.00 0.00 gapjunction M91236 membrane channel protein beta 5; Gjb5 100395_at 0.000.00 0.00 0.00 2.10 0.00 GLI-Kruppel family X99104 member GLI2; Gli297820_at 0.00 0.00 2.46 3.78 9.89 2.84 GLK AB027012 99141_at 0.00 0.000.00 1.91 1.71 4.95 activator protein; U09816 Gm2a 111347_at 0.00 0.000.00 2.18 2.61 3.02 UNK_AI842321 AI842321 112203_at 0.00 0.00 2.28 0.003.41 3.74 UNK_AI159117 AI159117 97227_at 0.00 0.00 0.00 0.00 2.05 0.00guanine nucleotide M63659 binding protein, alpha 12; Gna12 97195_at 0.000.00 0.00 0.00 1.55 2.31 binding protein, U38501 alpha inhibiting 1;Gnai1 99597_at 0.00 3.19 1.89 3.28 2.96 3.96 GNAI2 AI841629 99596_f_at0.00 1.55 0.00 2.57 2.74 2.78 binding protein, M13963 alpha inhibiting2; Gnai2 99598_g_at 0.00 1.78 1.70 2.78 2.19 2.94 GNAI2 AI84162998403_at 0.00 0.00 0.00 0.00 2.76 0.00 binding protein, X65026 relatedsequence 1; Gna-rs1 94854_g_at 0.00 0.00 1.55 2.04 2.09 2.16 guaninenucleotide U29055 binding protein, beta 1; Gnb1 97458_at 0.00 0.00 0.002.21 2.02 2.23 GNB1 AI845935 94853_at 0.00 0.00 0.00 2.38 1.75 2.56guanine nucleotide U29055 binding protein, beta 1; Gnb1 96911_at 0.001.70 0.00 2.58 2.86 2.20 guanine nucleotide U34960 binding protein, beta2; Gnb2 107026_at 0.00 0.00 1.56 1.38 2.66 2.01 UNK_AW123052 AW12305293949_at 0.00 0.00 0.00 1.26 2.32 1.69 guanine nucleotide M63658 bindingprotein, beta 4; Gnb4 99175_at 0.00 1.95 0.00 3.06 3.53 3.40 GNG10AI843396 100418_at 0.00 0.00 0.00 0.00 2.34 0.00 GNG2 AW123750 104469_at0.00 3.50 3.20 3.84 3.87 3.68 Gp38 M73748 100325_at 2.62 2.49 3.65 4.124.79 5.72 glycoprotein 49 M65027 A, glycoprotein 49 B; Gp49a, Gp49b92217_s_at 2.14 2.62 2.84 3.41 3.42 3.67 Gp49b U05265 100435_at 0.000.00 0.00 0.00 6.50 2.76 GPCR26 U13370 96978_at 0.00 0.00 0.00 0.00 2.312.20 GPH-PENDING AB025258 92611_at 0.00 1.62 2.76 2.64 3.18 2.91 P137U18773 102040_at 0.00 0.00 0.00 0.00 6.38 0.00 GPRK6 Y15798 104257_g_at1.81 3.32 4.39 2.84 3.70 4.44 UNK_AI120844 AI120844 93690_at 0.00 0.000.00 0.00 5.63 2.81 GRB10 AF022072 93691_s_at 0.00 0.00 0.00 1.82 5.282.39 receptor bound U18996 protein 10; Grb10 92263_at 0.00 0.00 0.003.94 7.69 6.29 leucine rich protein, AC002397 B7 gene; Lrpb7 94217_f_at0.00 1.72 0.00 2.30 2.06 1.45 leucine rich protein, AC002397 B7 gene;Lrpb7 103993_at 0.00 0.00 0.00 0.00 4.50 3.02 leucine rich protein,AC002397 B7 gene; Lrpb7 130710_at 0.00 0.00 0.00 0.00 2.21 3.04UNK_AA869432 AA869432 93066_at 0.00 2.00 3.08 4.01 3.19 5.73 CRN D1619595348_at 0.00 3.06 0.00 0.00 0.00 0.00 Gro1 J04596 108045_at 0.00 0.004.00 8.85 37.24 14.80 UNK_AA798520 AA798520 101060_at 0.00 1.98 2.324.79 4.52 3.76 reticulum protein; M73329 Erp 98052_at 0.00 0.00 0.002.10 3.20 2.28 GS15 AF003999 94369_at 0.00 0.00 0.00 0.00 2.95 3.81GSNPAT-PENDING AW123026 94811_s_at 0.00 0.00 0.00 3.37 1.72 0.00 factorIIH, AJ002366 polypeptide 1 (62 kD subunit); Gtf2h1 93588_at 0.00 0.000.00 3.44 3.31 4.17 Gtl3 Z54179 98410_at 0.00 0.00 0.00 2.35 1.93 2.75GTPI AJ007972 98950_at 0.00 0.00 0.00 1.95 1.89 2.29 GTR2 AB017616103038_at 0.00 0.00 0.00 1.95 2.54 2.11 guanylate cyclase L36860activator 1a (retina); Guca1a 97538_at 0.00 2.21 3.31 4.47 4.17 7.37GUS-S M19279 102688_f_at 0.00 0.00 0.00 0.00 17.31 0.00 GZMD X56990102728_f_at 0.00 0.00 0.00 0.00 15.71 0.00 GZME M36901 92866_at 0.002.07 0.00 2.67 2.11 4.52 H2-AA X52643 100998_at 0.00 3.08 0.00 3.81 2.273.97 H2-AB1 M21932 94805_f_at 0.00 2.32 2.24 3.40 2.34 1.33 UNK_M33988M33988 93019_at 0.00 0.00 1.29 2.00 3.96 1.92 HIST5-2AX Z35401 101954_at0.00 0.00 0.00 2.47 2.13 1.72 H2afz U70494 97541_f_at 0.00 0.00 0.002.94 2.21 4.21 D region locus 1; H2- X00246 D 97540_f_at 0.00 0.00 0.002.17 1.64 2.90 D region locus 1; H2- M69069 D 101886_f_at 0.00 1.56 1.672.67 2.22 3.64 H2-L X52490 98035_s_at 0.00 4.04 0.00 0.00 2.47 9.55H2-DMB1 U35330 98034_at 0.00 1.58 0.00 0.00 2.12 0.00 H2-DMB1 U3533094285_at 0.00 2.10 0.00 2.71 2.02 3.96 class II antigen E X00958 beta;H2-Eb1 97173_f_at 0.00 0.00 0.00 4.33 2.95 7.12 H2-K2 M27134 103371_at0.00 0.00 0.00 2.62 3.44 2.54 UNK_AF100956 AF100956 102161_f_at 0.001.46 0.00 3.22 2.08 4.39 H2-Q2 X58609 98438_f_at 0.00 0.00 0.00 2.741.78 3.55 H2-Q7 X16202 93865_s_at 0.00 0.00 2.00 2.91 2.15 2.95histocompatibility 2, M35244 T region locus 10, histocompatibility 2, Tregion locus 17, histocompatibility 2, T region locus 22,histocompatibility 2, T region locus 9; H2-T10, H2-T17, H2- T22, H2-T998472_at 0.00 0.00 2.30 3.40 2.50 4.96 H2-T23 Y00629 100708_at 0.00 0.000.00 2.88 2.50 2.60 H3 histone, family X13605 3B; H3f3b 111734_at 0.000.00 0.00 3.21 3.18 4.05 UNK_AW121301 AW121301 104125_at 0.00 0.00 0.002.35 1.70 1.64 HAIR-PENDING AA763673 92580_at 0.00 0.00 0.00 2.68 0.000.00 histidyl tRNA U39473 synthetase; Hars 98865_at 0.00 2.65 0.00 3.333.29 0.00 hyaluronan synthase U52524 2; Has2 105550_at 0.00 1.93 2.612.31 2.78 0.00 HAS2 AI122156 103286_at 0.00 0.00 0.00 2.02 3.13 0.00UNK_AB012611 AB012611 93483_at 2.86 5.24 2.12 3.21 10.07 3.83lemopoietic cell J03023 kinase; Hck 99461_at 1.98 5.10 3.27 2.70 2.630.00 hematopoietic cell X84797 specific Lyn substrate 1; Hcls1102851_s_at 0.00 2.75 5.77 5.45 2.90 4.43 HCPH M68902 96046_at 0.00 0.000.00 2.52 1.79 0.00 HDAC1 X98207 92730_at 0.00 0.00 0.00 2.16 0.00 0.00epidermal growth L07264 factor-like growth factor; Hegfl 97334_at 0.001.95 0.00 0.00 4.41 0.00 HES6 AW048812 94840_at 0.00 0.00 0.00 2.49 2.457.00 Hexa U05837 101913_at 0.00 2.34 0.00 3.35 3.35 1.98 HEY1 AW21429898628_f_at 0.00 1.91 0.00 3.83 3.98 3.08 factor 1, alpha AF003695subunit; Hif1a 98629_f_at 0.00 1.97 0.00 3.82 3.68 3.30 HIF1A Y0908593250_r_at 0.00 4.01 0.00 7.33 4.74 4.32 HMG2 X67668 104285_at 0.00 0.000.00 0.00 4.78 0.00 methylglutaryl- M62766 Coenzyme A reductase; Hmgcr96699_at 0.00 1.71 1.85 3.26 3.43 2.91 high mobility group X53476protein 14; Hmg14 101589_at 0.00 2.37 2.80 4.52 3.86 3.35 high mobilitygroup X12944 protein 17; Hmg17 93276_at 0.00 1.63 2.23 2.32 2.69 2.00neurological U90123 expressed sequence 1; Hn1 97272_at 0.00 1.75 2.193.44 4.86 3.11 HNRPA1 M99167 94303_at 0.00 0.57 2.05 0.00 1.69 3.51nuclear U11274 ribonucleoprotein D; Hnrpd 101485_at 0.00 0.00 0.00 5.333.02 2.04 HNRPDL AW124859 93990_at 0.00 0.00 0.00 2.21 1.76 1.61 0Y14196 95232_at 0.00 0.00 0.00 1.94 1.75 2.79 HNRPL AB009392 96092_at0.00 5.71 8.04 13.88 15.44 15.06 haptoglobin; Hp M96827 93351_at 0.000.00 0.00 0.00 4.99 7.54 hydroxyprostaglandin U44389 dehydrogenase 15(NAD); Hpgd 102306_at 0.00 0.00 0.00 3.65 4.58 3.02 HS2ST1 AF060178101962_at 0.00 0.00 0.00 0.00 1.86 2.30 HSC70 AI854884 97261_at 0.001.77 0.00 0.00 2.16 2.28 HSJ2 AF055664 100353_g_at 0.00 2.82 0.00 0.002.79 0.00 HSPA4 AA919208 99816_at 0.00 0.00 0.00 0.00 2.43 0.00 heatshock protein, M20567 70 kDa 2; Hsp70-2 95282_at 0.00 2.04 0.00 2.821.71 1.47 heat shock protein, J04633 86 kDa 1; Hsp86-1 101955_at 0.001.92 1.98 3.00 2.30 1.78 GRP78 AJ002387 96254_at 0.00 1.99 0.00 0.003.44 3.03 HSPF1 AB028272 101399_at 0.00 0.00 0.00 0.00 2.72 0.00pertecan (heparan M77174 sulfate proteoglycan 2); Hspg2 94236_at 0.000.00 0.00 0.00 2.44 1.97 UNK_AI838152 AI838152 100476_at 0.00 0.00 0.000.82 135.39 85.11 IBSP L20232 100050_at 2.63 14.09 11.54 10.70 4.20 6.22inhibitor of DNA M31885 binding 1; Idb1 92614_at 4.55 9.82 5.87 7.789.53 9.08 inhibitor of DNA M60523 binding 3; Idb3 99109_at 0.00 0.000.00 3.13 2.22 1.86 immediate early M59821 response 2; Ier2 94384_at0.00 1.56 0.00 3.55 1.73 2.13 immediate early X67644 response 3; Ier392251_f_at 0.00 1.84 2.88 3.49 2.71 3.51 UNK_AA960657 AA96065794224_s_at 0.00 2.12 3.85 3.55 2.35 2.62 UNK_M74123 M74123 98465_f_at0.00 2.15 4.38 5.23 3.24 3.50 interferon activated M31419 gene 204;Ifi204 104750_at 0.00 3.40 7.66 4.69 2.10 4.67 interferon gamma M63630inducible protein, 47 kDa; Ifi47 100981_at 0.00 0.00 8.75 0.00 3.37 2.08interferon-induced U43084 protein with tetratricopeptide repeats 1;Ifit1 112340_at 0.00 0.00 4.49 1.51 0.00 0.00 UNK_AA178653 AA178653103639_at 0.00 0.00 4.82 7.01 2.67 2.35 interferon-induced U43085protein with tetratricopeptide repeats 2; Ifit2 93956_at 0.00 0.00 4.256.35 0.00 0.00 IFIT3 U43086 100483_at 0.00 0.00 2.24 3.74 4.92 4.19interferon (alpha and M89641 beta) receptor Ifnar 101014_at 0.00 0.003.34 0.00 2.93 3.31 IFNAR2 Y09864 101015_s_at 0.00 2.18 1.84 1.70 3.805.13 IFNAR2 AF013486 100552_at 0.00 0.00 0.00 3.89 1.88 2.16 IFNGRM28233 95546_g_at 0.00 0.00 0.00 3.10 6.23 5.82 insulin-like growthX04480 factor 1; Igf1 98623_g_at 0.00 0.00 0.00 0.00 3.20 2.42 IGF2X71922 95082_at 0.00 0.00 0.00 0.00 2.92 4.18 IGFBP3 AI842277 95083_at0.00 0.00 0.00 0.00 7.76 6.72 factor binding X81581 protein 3; Igfbp3101571_g_at 0.00 0.00 0.00 3.58 7.05 8.40 IGFBP4 X76066 103949_at 0.000.00 0.00 0.00 3.03 0.00 Indian hedgehog X76291 homolog, (Drosophila);Ihh 101054_at 0.00 1.83 0.00 2.41 2.02 3.39 Ia-associated X00496invariant chain; li 96764_at −2.18 0.00 4.23 4.92 2.47 10.03UNK_AJ007971 AJ007971 111615_at 0.00 0.00 0.00 0.00 3.13 0.00 IKBKBAW209118 99491_at 0.00 2.16 1.76 1.96 3.49 3.19 interleukin 10 U53696receptor, beta; Il10rb 99991_at 0.00 2.79 0.00 0.00 1.72 3.32interleukin 17 U31993 receptor; Il17r 103486_at 0.63 2.39 2.75 3.67 2.174.47 Il1b M15131 93914_at 0.00 4.38 0.00 3.94 3.09 3.44 interleukin 1M20658 receptor, type I; Il1r1 93871_at 0.00 0.00 0.00 4.89 1.33 3.75IL1RN L32838 102021_at 3.54 27.39 6.36 13.28 10.97 6.34 interleukin 4M27960 receptor, alpha; Il4ra 102218_at 0.00 2.71 0.00 1.55 0.00 0.00interteukin 6; Il6 X54542 101499_at 0.00 0.00 0.00 3.26 2.76 2.65 ILKU94479 100277_at 0.00 0.00 2.28 5.04 4.35 0.00 inhibin beta-A; InhbaX69619 94399_at 0.00 0.00 0.00 0.00 1.14 2.02 INPP5B AI843172 102884_at0.00 2.24 1.00 2.31 1.62 1.57 polyphosphate-5- U51742 phosphatase, 145kDa; Inpp5d 100561_at 0.00 1.75 1.98 2.97 3.51 4.48 IQGAP1 AW20909899103_at 0.00 0.00 0.00 0.00 2.24 0.00 IRF3 AF036341 93425_at 0.00 0.000.00 2.88 0.00 0.00 interferon regulatory AF028725 factor 5; Irf5104669_at 0.00 0.00 1.37 2.31 3.90 2.76 interferon regulatory U73037factor 7; Irf7 98822_at 1.83 2.50 7.89 17.45 7.07 5.85 protein (15 kDa);X56602 Isg15 103634_at 0.00 2.12 0.00 3.40 4.00 3.66 interferondependent U51992 positive acting transcription factor 3 gamma; Isgf3g99010_at 0.00 1.49 0.00 2.51 4.56 3.66 ISLR AB024538 98366_at 0.00 0.000.00 0.00 2.16 3.20 integrin alpha V U14135 (Cd51); Itgav 100124_r_at0.00 0.00 0.00 2.19 1.92 2.34 ITGB1 X15202 102353_at 1.84 2.21 2.43 2.513.29 7.22 ITGB2 M31039 94826_at 0.00 1.64 1.82 2.47 2.59 1.69 ITGB4BPY11460 100601_at 0.00 0.00 0.00 0.00 2.93 0.00 ITGB5 AF022110 103611_at0.00 1.73 0.00 2.11 2.33 2.77 ITGP AB012693 98922_at 0.00 0.00 0.00 0.002.69 2.27 intergral membrane L34260 protein 1; Itm1 93511_at 0.00 0.000.00 0.00 2.04 0.00 integral membrane L38971 protein 2; Itm2 96283_at0.00 0.00 0.00 4.19 9.42 7.02 UNK_AI849180 AI849180 99509_s_at 0.00 0.000.00 0.00 6.28 0.00 JAK3 L40172 103816_at 0.00 0.00 0.00 1.96 1.74 2.64JCAM U89915 102362_i_at 2.25 5.90 2.20 8.24 4.87 0.00 Junb U20735102363_r_at 0.00 6.13 3.53 14.86 4.92 0.00 Junb U20735 102364_at 0.000.00 0.00 0.00 2.24 2.09 JUND1 J04509 114683_at 0.00 0.00 0.00 0.00 2.124.85 KAP AW125126 102892_at 0.00 2.18 0.00 0.00 1.30 1.61 KCNAB2 U65592109931_at 0.00 0.00 0.00 0.00 4.27 2.96 UNK_AW214619 AW214619 102335_at0.00 0.00 0.00 0.00 4.22 5.08 KCNK1 AF033017 104652_at 0.00 0.00 0.000.00 1.71 3.71 KCNK2 AI849601 102198_at 0.00 5.02 4.23 5.49 6.12 6.03KCNN4 AF042487 102644_at 0.00 2.13 2.16 3.29 3.28 4.38 derivedtranscript 1; U13371 Kdt1 106026_at 0.00 0.00 0.00 2.22 1.11 0.00 KELCHLAI845205 99541_at 0.00 0.00 2.42 2.19 2.31 1.50 KIFL1 AJ223293 94276_at0.00 2.50 0.00 2.52 1.93 2.89 UNK_AF064635 AF064635 100010_at 0.00 0.000.00 0.00 2.38 2.04 Kruppel-like factor 3 U36340 (basic); Klf3 99622_at0.00 0.00 0.00 0.00 2.46 2.79 Kruppel-like factor 4 U20344 (gut); Klf4102707_f_at 0.00 0.00 3.80 0.00 0.00 0.00 kallikrein binding X61597protein; Klkbp 93677_at 0.00 0.00 0.00 1.68 2.07 1.74 KLRD1 AF03031192790_at 0.00 3.36 3.06 3.84 3.02 2.72 (importin) alpha 2; D55720 Kpna297991_at 0.00 2.56 0.00 0.00 2.22 0.00 Kirsten rat sarcoma X02452oncogene 2, expressed; Kras2 97909_at 0.00 5.50 6.71 11.66 11.44 8.79UNK_AI838080 AI838080 104587_at 0.00 0.00 0.00 3.06 4.57 4.63 Lama4U69176 101948_at 0.00 0.00 0.00 2.83 5.29 1.96 LAMB1-1 X05212 140322_at0.00 0.00 2.48 2.50 2.39 2.59 LAMP2 AW018326 100136_at 0.00 0.00 0.002.49 2.82 2.87 LAMP2 M32017 100012_at 0.00 2.03 3.10 3.09 4.43 8.86associated protein U29539 transmembrane 5; Laptm5 93793_at 0.00 1.731.73 3.30 4.36 5.96 LASP1 AW122780 93930_at 0.00 0.00 0.00 1.83 4.324.37 LIM and SH3 protein U58882 1; Lasp1 114629_at 0.00 0.68 2.63 3.491.80 2.04 UNK_AW124408 AW124408 102957_at 0.00 3.04 0.00 3.19 2.47 4.63lymphocyte cytosolic U20159 protein 2; Lcp2 93682_at 0.00 0.00 0.00 0.002.02 1.93 LDB3 U89489 93797_g_at 0.00 2.55 1.84 3.48 3.05 2.86 TCFL1AW123952 93798_at 0.00 2.67 0.00 3.36 3.02 3.32 TCFL1 AI839988 93600_at0.00 1.83 2.22 2.93 3.37 4.78 LEPR AJ011565 100431_at 0.00 0.00 0.000.00 4.53 5.21 leptin receptor Lepr U42467 95706_at 0.00 0.00 1.74 4.153.83 10.29 binding, soluble 3; X16834 Lgals3 103335_at 0.00 1.81 2.082.99 2.89 2.47 binding, soluble 9; U55060 Lgals9 104659_g_at 0.00 0.000.00 0.00 5.33 11.04 LIFR D17444 104657_at 0.00 0.00 0.00 0.00 1.77 3.26leukemia inhibitory D26177 factor receptor; Lifr 102123_at 0.00 0.000.00 3.18 1.67 3.11 UNK_Z31689 Z31689 98059_s_at 0.00 2.68 2.74 4.633.92 2.97 lamin A; Lmna D49733 93666_at 0.00 0.00 0.00 0.00 2.00 0.00LMO2 M64360 95069_at 0.00 0.00 0.00 0.00 3.14 2.18 UNK_AA940430 AA94043098122_at 0.00 0.00 0.00 0.00 2.19 1.94 LMO4 AF074600 93939_at 0.00 0.000.00 0.00 3.16 1.74 LNK U89993 93885_g_at 0.00 0.00 0.00 0.00 1.92 3.59LOC53423 AB034693 94997_at 0.00 0.00 0.00 0.00 1.76 2.65 LOC53423AF060883 101518_at 0.00 0.00 0.00 3.58 5.95 4.14 uterine protein; U38981LOC55978 92569_f_at 0.00 0.00 2.09 2.56 2.98 0.00 LOC55989 AF053232115414_at 0.00 2.55 0.00 2.70 0.00 0.00 UNK_AI849017 AI849017 104524_at0.00 1.64 1.93 0.00 2.21 3.77 UNK_AI842825 AI842825 96260_at 0.00 0.001.44 2.63 2.92 3.01 UNK_AB021491 AB021491 116843_at 0.00 0.00 0.00 0.062.61 2.86 UNK_AW045920 AW045920 93753_at 0.00 1.85 1.80 3.48 2.78 4.85UNK_AI852632 AI852632 109105_i_at 0.00 0.00 0.00 1.57 4.79 4.72UNK_AW122202 AW122202 109106_f_at 0.00 0.00 0.00 2.28 2.86 1.89UNK_AW122202 AW122202 111200_at 0.00 0.00 0.00 0.00 2.70 0.00UNK_AA726446 AA726446 96139_at 0.00 0.00 0.00 0.00 6.31 0.00UNK_AF001797 AF001797 113180_at 0.00 0.00 0.00 0.00 2.75 0.00UNK_AW125855 AW125855 113101_f_at 0.00 0.00 0.00 0.00 2.07 0.00UNK_AI644869 AI644869 113215_i_at 0.00 0.00 0.00 0.00 2.52 1.42UNK_AI850449 AI850449 113231_at 0.00 0.00 0.00 2.09 2.43 2.31UNK_AI854099 AI854099 111385_at 0.00 0.00 0.00 0.00 3.75 0.00UNK_AA734127 AA734127 138455_at 0.00 0.00 0.00 4.25 4.54 7.46UNK_AI847317 AI847317 107403_at 0.00 0.00 0.00 0.00 5.41 2.12UNK_AW047735 AW047735 111239_at 0.00 0.00 0.00 1.67 3.73 1.58UNK_AI428160 AI428160 100408_at 0.00 0.00 0.00 0.00 2.27 0.00UNK_AA839465 AA839465 116332_at 0.00 0.00 0.00 0.00 2.64 0.00UNK_AW228823 AW228823 111391_at 0.00 2.16 0.00 2.12 4.09 3.51UNK_AI846729 AI846729 101073_at 0.00 0.00 0.00 1.86 1.89 2.07 lowdensity X67469 lipoprotein receptor related protein; Lrp 92564_at 0.000.00 0.00 0.00 2.44 1.96 LRRFIP1 AI891475 104093_at 0.00 1.65 0.00 3.087.88 3.15 LSP1 D49691 103571_at 0.00 2.58 2.53 4.71 12.61 7.37 LST1U72644 100540_at 0.00 0.00 0.00 1.94 2.39 2.10 leukotriene A4 M63848hydrolase; Lta4h 103209_at 0.00 0.00 0.00 0.00 2.04 0.00 UNK_AF022889AF022889 92335_at 2.27 5.35 4.42 7.37 8.46 3.49 growth factor betaAF004874 binding protein 2; Ltbp2 96090_a_at 0.00 0.00 0.00 0.00 1.482.59 UNK_AI255972 AI255972 93353_at 0.00 0.00 0.00 2.37 4.25 4.32lumican; Lum AF013262 96065_at 0.00 2.48 2.99 4.79 10.45 4.81 latexin;Lxn D88769 114822_f_at 0.00 0.00 0.00 2.23 1.71 2.53 UNK_AA762251AA762251 100771_at 0.00 2.32 0.00 3.22 2.64 0.00 LY57 AF068182100772_g_at 0.00 0.00 0.00 3.32 3.38 0.00 LY57 AF068182 93078_at 0.000.00 0.00 2.01 0.00 0.00 LY6 X04653 101487_f_at 0.00 1.52 1.77 2.89 2.342.43 LY6E U47737 94425_at 0.00 2.66 1.85 3.26 2.53 2.88 LY86 AB007599100468_g_at 0.00 1.84 2.02 2.66 1.65 2.94 lymphoblastomic X57687leukemia; Lyl1 100467_at 0.00 0.00 2.64 0.00 0.00 0.00 lymphoblastomicX57687 leukemia; Lyl1 103349_at 0.00 2.70 2.60 0.00 4.26 0.00 viral(v-yes-1) M57696 oncogene homolog; Lyn 101753_s_at 0.00 1.77 2.34 3.142.90 3.36 LZP-S X51547 100477_at 0.00 3.23 0.00 7.39 9.49 5.76hypothetical protein M32486 19.5; p19.5 92847_s_at 0.00 1.93 1.57 3.011.89 3.90 M6PR X56831 96865_at 0.00 0.00 1.70 2.61 3.59 3.60 alaninerich protein M60474 kinase C substrate; Macs 99632_at 0.00 3.64 3.715.79 4.99 3.29 MAD2L1 U83902 99024_at 0.00 0.00 0.00 2.37 3.96 3.22 Maxdimerization U32395 protein 4; Mad4 102983_at 0.00 0.00 0.00 2.26 2.672.46 MADH1 U58992 102984_g_at 0.00 0.00 0.00 0.00 2.46 2.38 MADH1 U58992104536_at 0.00 0.00 0.00 2.18 2.08 2.27 MADH2 U60530 104220_at 2.64 2.732.60 2.03 1.86 1.93 MADH6 AF010133 114338_at 0.00 2.06 2.77 3.20 3.214.58 MAFB AI642664 102204_at 0.00 2.04 0.00 1.93 3.78 3.95musculoaponeurotic L36435 fibrosarcoma oncogene family, protein B(avian); Mafb 117143_s_at 0.00 0.00 0.00 2.70 2.61 3.69 MAFB AW213708117144_r_at 0.00 0.00 0.00 0.00 4.02 3.31 MAFB AW213708 105228_at 0.001.54 0.00 1.91 3.85 3.66 MAN1B AI528764 110305_at 0.00 0.00 0.00 0.004.70 3.60 MAN1B AA960561 104628_at 0.00 1.85 0.00 4.09 2.33 3.10mannosidase 2, X61172 alpha 1; Man2a1 99562_at 0.00 2.00 2.50 3.15 3.164.31 MAN2B1 U87240 102195_at 0.00 0.00 2.76 2.19 2.65 3.58 proteinkinase U88984 kinase kinase kinase 4; Map4k4 103416_at 0.00 0.00 0.002.14 1.55 1.98 MAPK6 AI844810 98475_at 0.00 0.00 0.00 3.59 8.68 5.06matrilin 2; Matn2 U69262 102089_at 0.00 0.00 0.00 0.00 11.72 0.00 MATN3Y10521 96835_at 0.00 0.00 0.00 0.00 23.39 8.68 MATN4 AJ010984 99095_at0.00 0.00 0.00 1.82 2.24 2.47 Max protein; Max M63903 96767_at 0.00 1.831.99 3.73 4.04 3.18 MBC2 AF098633 100062_at 0.00 2.91 3.11 3.83 3.442.47 maintenance X62154 deficient (S. cerevisiae); Mcmd 93112_at 0.000.00 1.92 0.00 2.36 0.00 MCMD2 D86725 93041_at 0.00 7.24 7.49 6.58 4.252.16 maintenance D26089 deficient 4 homolog (S. cerevisiae); Mcmd4100156_at 0.00 7.39 9.72 7.89 7.48 2.57 maintenance D26090 deficient 5(S. cerevisiae); McmdS 93356_at 0.00 0.00 0.00 0.00 2.28 2.63maintenance D26091 deficient 7 (S. cerevisiae); Mcmd7 99133_at 0.00 2.081.76 3.23 3.10 2.32 monoclonal X14309 antibodies 4F2; Mdu1 103584_at0.00 2.17 2.27 3.29 4.01 4.66 UNK_AW124334 AW124334 92607_at 0.00 0.000.00 4.80 35.79 13.98 MEST AF017994 101095_at 0.00 0.00 0.00 0.00 7.2112.75 associated protein 2; L23769 Mfap2 131248_at 1.92 0.00 0.00 2.864.34 2.62 MFAP5-PENDING AI608002 99518_at 1.91 0.00 0.00 2.66 2.54 1.97MFAP5-PENDING AW121179 92880_at 0.00 0.00 0.00 0.00 2.78 1.95 factor 8protein; M38337 Mfge8 103080_at 0.00 2.28 3.11 3.79 2.29 3.86 IFN-gammaU15635 induced; Mg11 110672_at 0.00 0.00 0.00 2.18 0.00 0.00 MGLAW049068 93866_s_at 0.00 0.00 0.00 0.00 2.01 2.44 matrix gamma- D00613carboxyglutamate (gla) protein; Mglap 104410_at 0.00 0.00 0.00 3.62 2.312.44 UNK_AW124785 AW124785 99457_at 0.00 4.86 5.97 6.25 6.68 4.02antigen identified by X82786 monoclonal antibody Ki 67; Mki67101069_g_at 0.00 1.70 0.00 0.00 2.03 3.10 MKRN1 AA656621 97203_at 0.004.21 3.45 4.84 7.71 7.84 MLP X61399 92331_at 0.00 0.00 0.00 0.00 5.673.92 endopeptidase; M81591 Mme 98280_at 0.00 0.00 0.00 0.00 1.80 2.98UNK_AB021228 AB021228 112880_at 0.00 0.00 0.00 2.93 7.30 4.28 MMP23AA144420 98833_at 0.00 0.00 0.00 0.00 0.53 2.49 metalloproteinase 3;X66402 Mmp3 99957_at 0.00 0.00 0.00 39.03 26.93 96.46 MMP9 X7279595045_at 0.00 1.45 0.00 3.50 3.07 2.57 UNK_AI844469 AI844469 131220_f_at0.00 0.00 0.00 0.00 2.24 0.00 UNK_AW123699 AW123699 95951_at 0.00 3.672.20 3.26 2.12 1.72 MPCL AF061272 99071_at 0.00 1.53 2.18 3.44 4.43 9.63expressed gene 1; L20315 Mpeg1 94857_at 0.00 0.00 0.00 0.00 2.55 2.53N-methylpurine-DNA U10420 glycosylase; Mpg 97803_at 0.00 2.84 3.15 3.772.11 3.63 membrane protein, U38196 palmitoylated (55 kDa); Mpp1103226_at 3.09 5.30 3.98 3.64 2.84 2.41 mannose receptor, Z11974 C type1; Mrc1 100759_at 0.00 0.00 0.00 0.00 7.71 3.67 mannose receptor, U56734C type 2; Mrc2 96633_s_at 0.00 0.00 0.00 2.25 2.20 2.01 Sid393p; Sid393pAA529583 96632_at 0.00 0.00 0.00 2.23 1.96 1.69 UNK_AB025049 AB02504996120_at 0.00 0.00 0.00 2.06 1.64 1.99 MRJ-PENDING AW124750 98373_at0.00 2.29 3.59 2.69 0.00 0.00 UNK_AI462516 AI462516 93234_at 0.00 0.000.00 0.00 3.55 0.00 MSC AF087035 93602_at 0.00 2.16 0.00 0.00 3.26 2.23UNK_AF074714 AF074714 93573_at 0.00 2.93 2.31 8.18 4.56 10.01 Mt1 V00835101561_at 0.00 2.89 2.70 5.96 4.03 7.42 Mt2 K02236 108780_at 0.00 2.322.52 3.20 4.77 3.11 UNK_AI845395 AI845395 100046_at 0.00 0.00 3.84 6.204.36 3.26 folate J04627 dehydrogenase (NAD+ dependent),methenyltetrahydro- folate 98417_at 2.13 0.00 2.31 2.78 1.96 1.90 MX1M21038 96285_at 0.00 1.55 1.71 3.13 2.84 2.61 MYADM AJ001616 104712_at0.00 2.70 2.99 2.96 4.49 2.41 myelocytomatosis L00039 oncogene; Myc102430_at 0.00 4.68 0.00 4.96 6.64 4.14 differentiation X51397 primaryresponse gene 88; Myd88 106557_at 0.00 0.00 0.00 3.15 5.61 4.03UNK_AI132668 AI132668 100923_at 0.00 0.00 0.00 0.00 1.80 2.22 MYO10AJ249706 98409_at 0.00 0.00 1.41 2.83 7.66 9.17 myosin Ib; Myo1b L0092395506_at 0.00 0.00 0.00 0.00 2.37 0.00 MYO1C U96723 101708_at 0.00 0.000.00 0.00 1.61 2.32 myosin If; Myo1f X97650 98968_at 0.00 1.84 2.19 1.681.71 2.15 myosin Va; Myo5a X57377 94713_at 0.00 0.00 0.00 0.00 2.66 4.15myosin VIIa; Myo7a U81453 114776_at 0.00 0.00 0.00 3.11 8.64 5.61 MYO9BAA739159 102986_at 3.53 3.84 2.32 2.76 2.31 0.00 MYOD1 M18779 103053_at0.00 3.08 0.00 8.00 4.91 0.00 MYOG X15784 94408_at 0.00 0.00 0.00 2.012.30 3.18 Ngfi-A binding U47008 protein 1; Nab1 100962_at 0.00 0.00 1.992.66 3.48 3.63 Ngfi-A binding U47543 protein 2; Nab2 103637_at 0.00 0.000.00 0.00 4.22 4.03 NAGA AJ223966 93373_at 0.00 0.00 0.00 0.00 3.21 6.08alpha-N- U85247 acetylglucosaminidase (Sanfilippo disease IIIB); Naglu98587_at 0.00 1.60 2.17 2.65 2.40 1.80 assembly protein 1- X61449 like1; Nap1I1 101108_at 0.00 4.08 0.00 0.00 0.00 0.00 autoantigenic spermAF034610 protein (histone- binding); Nasp 100153_at 0.00 0.00 1.32 4.104.06 2.79 neural cell adhesion X15052 molecule; Ncam 99633_at 0.00 0.000.00 0.00 2.26 0.00 NCDN-PENDING AB017608 102326_at 0.00 4.13 0.00 0.001.95 2.92 NCF2 AB002664 100144_at 0.00 0.00 0.00 2.36 2.06 0.00nucleolin; Ncl X07699 94047_at 0.00 1.49 0.00 2.17 2.44 3.23UNK_AW122935 AW122935 101059_at 0.00 0.00 0.00 2.49 2.14 0.00 NDN D76440100472_at 0.00 0.00 0.00 3.04 2.49 1.99 NPC derived proline D10727 richprotein 1; Ndpp1 107467_at 0.00 0.00 0.00 2.05 2.13 1.80 UNK_AW047444AW047444 92518_at 0.00 0.00 0.00 0.00 2.48 0.00 NEO1 Y09535 103549_at0.00 0.00 0.00 1.88 2.33 0.00 NES AW061260 115217_at 0.00 0.00 0.00 0.002.02 3.11 NFAT5 AI852272 102209_at 0.00 0.00 3.02 6.06 3.92 12.16 NFATC1AF087434 115215_at 0.00 0.00 0.00 5.96 7.00 13.80 UNK_AA638441 M63844198427_s_at 0.00 0.00 0.00 2.48 1.83 2.18 NFKB1 M57999 100469_at 0.000.00 0.00 2.00 2.53 3.49 NFYA D78642 93563_s_at 0.00 2.18 3.71 4.33 5.303.48 NID2 AB017202 93318_at 0.00 0.00 3.63 0.00 1.52 0.00 NINJ1 U9151392794_f_at 0.00 0.00 1.84 0.00 2.49 1.46 NME1 M35970 102047_at 0.00 0.000.00 2.17 0.00 0.00 NMT1 AF043326 101473_at 0.00 0.00 0.00 0.00 7.665.81 NNMT U86108 104132_at 0.00 0.00 0.00 2.32 3.69 0.00 NOC4 AW047276106115_at 0.00 0.00 0.00 2.39 2.08 0.00 UNK_AI849335 AI849335 102028_at0.00 0.00 0.00 4.05 2.85 3.43 NORE1 AF053959 100507_at 0.00 0.00 0.002.01 4.45 6.67 nephroblastoma Y09257 overexpressed gene; Nov 114812_at0.00 0.00 0.00 2.08 6.43 3.89 UNK_AA869278 AA869278 99564_at 0.00 3.623.98 4.26 2.21 2.67 NP95 D87908 92626_at 0.00 0.00 0.00 3.12 3.55 2.70differentiation and X67209 control gene 1; Npdc1 101634_at 0.00 0.001.77 2.55 2.14 0.00 Npm1 M33212 102796_at 0.00 3.11 0.00 0.00 0.00 0.00Npm3 U64450 101168_at 0.00 0.00 0.00 2.07 2.52 1.94 neoplastic Z31360progression 1; Npn1 93202_at 0.00 0.00 0.00 0.00 2.18 1.62 5′nucleotidase; Nt5 L12059 96666_at 0.00 0.00 0.00 0.00 4.20 0.00N-terminal Asn U57692 amidase; Ntan1 94528_at 1.73 3.32 1.59 1.72 1.900.00 NUBP1 AI846206 94839_at 0.00 0.00 0.00 2.37 2.60 2.29 nucleobindin;Nucb M96823 102197_at 0.00 0.00 0.00 2.38 3.20 2.50 NUCB2 AJ222586101593_at 0.00 0.00 0.00 0.00 3.55 0.00 UNK_AI851454 AI851454 108579_at0.00 2.97 0.00 2.53 5.55 2.93 NUDT5 AI854177 93046_at 0.00 0.00 0.000.00 3.03 1.95 UNK_AW045233 AW045233 102231_at 0.00 0.00 0.00 0.00 7.533.00 OASIS-PENDING AB017614 107525_at 0.00 2.46 5.90 6.26 4.94 5.61 OASLAW211637 101002_at 0.00 2.02 0.00 2.36 1.89 1.67 decarboxylase AF032128antizyme inhibitor; 99549_at 0.00 −3.17 0.00 0.00 3.34 2.12 osteoglycin;Ogn D31951 93369_at 0.00 0.00 0.00 0.00 9.11 5.81 osteomodulin; OmdAB007848 95712_at 0.00 2.64 0.00 3.22 2.28 1.84 UNK_AW045261 AW04526196093_at 0.00 0.00 0.00 3.36 0.00 0.00 UNK_AI842705 AI842705 117253_at0.00 0.00 0.00 1.90 3.19 0.00 UNK_AI845729 AI845729 100437_g_at 0.000.00 0.00 3.83 0.00 0.00 Orm1 M27008 92593_at 2.42 2.26 4.11 5.43 13.5619.79 osteoblast specific D13664 factor 2; OSF-2 102255_at 0.00 0.000.00 3.29 2.68 3.26 OSMR AB015978 100138_f_at 0.00 1.82 2.20 0.00 2.880.00 similar to human X52102 SYK interacting protein; p16K 95586_at 0.000.00 3.82 3.90 3.26 1.84 P2RX4 AF089751 96016_at 0.00 2.47 0.00 6.194.91 2.57 P40-8 AW045665 104139_at 0.00 0.00 0.00 1.90 2.21 1.822-oxoglutarate 4- U16162 dioxygenase (proline 4-hydroxylase), alpha 1polypeptide; P4ha1 98983_at 0.00 0.00 0.00 2.64 5.05 2.80 2-oxoglutarate4- U16163 dioxygenase (proline 4-hydroxylase), alpha II polypeptide;P4ha2 100720_at 0.00 1.59 2.28 2.36 3.73 2.53 protein, cytoplasmicX65553 1; Pabpc1 98021_at 0.00 0.00 0.00 0.00 2.39 0.00 0 D1433699023_at 0.00 1.65 0.00 4.28 2.73 0.00 factor U57747 acetylhydrolase,isoform 1b, alpha2 subunit; Pafah1b2 100576_at 0.00 0.00 0.00 1.95 2.292.64 factor U57746 acetylhydrolase, isoform 1b, alpha1 subunit; Pafah1b3114355_at 0.00 0.00 2.27 5.58 4.79 0.00 PANX1 AI847747 93298_at 0.000.00 0.00 0.00 3.57 3.43 phosphoadenosine U34883 5′-phosphosulfatesynthase 1; Papss1 96713_at 0.00 0.00 0.00 0.00 5.09 4.94 PAPSS2AF052453 93615_at 0.00 1.75 0.00 2.33 2.68 2.35 pre B-cell leukemiaAF020200 transcription factor 3; Pbx3 94449_at 0.00 0.00 0.00 0.00 2.503.46 PCDH13 AI854522 102280_at 0.00 0.00 0.00 0.00 1.82 3.45 PCDH7AB006758 102781_at 0.00 0.00 0.00 0.00 2.31 2.76 enhanced U37351expression; PCEE 109761_g_at 0.00 0.00 0.00 2.91 5.10 0.00 UNK_AI848972AI848972 101065_at 0.00 3.07 2.87 3.72 2.58 2.41 PCNA X57800 93349_at0.00 0.00 0.00 3.50 6.60 6.15 proteinase enhancer X57337 protein; Pcolce92192_s_at 0.00 0.00 2.04 3.28 4.63 2.79 PCSK5 D12619 101196_at 0.000.00 0.00 0.00 2.74 3.02 convertase D50060 subtilisin/kexin type 6;Pcsk6 95412_at 0.00 0.00 0.00 2.35 2.36 2.10 programmed cell U49112death 6; Pdcd6 96252_at 0.00 1.55 0.00 2.17 2.00 1.80 PDCD6IP AJ00507393382_at 0.00 0.00 0.00 0.00 2.51 0.00 PDE1B1 AF023343 116964_at 0.000.00 0.00 6.04 14.08 9.38 UNK_AI851805 AI851805 93574_at 0.00 0.00 1.713.31 3.42 4.08 SDF3 AF036164 115553_at 0.00 0.00 2.11 2.15 0.00 0.00UNK_AI841779 AI841779 101451_at 0.00 0.00 0.00 2.15 2.01 3.16 PEG3AF038939 96765_at 0.00 0.00 0.00 2.41 2.67 1.76 PEG3 AW120874 94516_f_at0.00 0.00 0.00 0.00 5.97 3.99 PENK2 M55181 101468_at 2.20 3.94 4.04 4.103.07 1.92 properdin factor, X12905 complement; Pfc 97834_g_at 0.00 2.072.29 3.11 2.38 2.29 UNK_AI853802 AI853802 97833_at 0.00 0.00 0.00 2.772.41 0.00 UNK_AI853802 AI853802 93421_at 0.00 3.19 0.00 3.98 5.66 4.45PFTAIRE protein AF033655 kinase 1; Pftk1 101585_at 0.00 0.00 2.28 2.715.13 6.27 PGRMC-PENDING AF042491 94406_at 0.00 0.00 0.00 0.00 6.01 4.58PHTF AJ242864 93708_at 0.00 0.00 0.00 0.00 2.16 1.78 PIAS3 AF03408092312_at 0.00 0.00 0.00 0.00 3.14 0.00 PIK3C2A U55772 96592_at 0.00 0.001.93 0.00 2.15 2.21 phosphatidylinositol U50413 3-kinase, regulatorysubunit, polypeptide 1 (p85 alpha); Pik3r1 101926_at 0.00 0.00 0.00 0.002.74 0.00 proviral integration L41495 site 2; Pim2 95358_at 0.00 0.000.00 1.63 1.80 2.05 UNK_AI843864 AI843864 100328_s_at 4.40 8.50 5.1712.16 2.38 11.48 PIRA3 U96684 98003_at 0.00 2.48 0.00 3.55 3.42 3.45PIRB AF038149 102696_s_at 0.00 0.00 2.49 0.00 2.01 2.44 UNK_AI747899AI747899 101461_f_at 0.00 0.00 0.00 2.09 2.39 2.19 PJA1 U06944 104531_at0.00 1.31 1.42 1.63 2.40 2.42 protein kinase C, X60304 delta; Pkcd97375_at 0.00 0.00 0.00 0.00 2.90 3.20 disease 1 homolog; U70209 Pkd1100951_at 0.00 0.00 0.00 2.13 3.19 3.22 polycystic kidney AF014010disease 2; Pkd2 99513_at 1.58 5.00 0.00 10.15 10.27 5.24 phospholipaseA2, M72394 group 4; Pla2g4 94147_at 4.28 9.58 8.85 11.13 4.61 4.14activator inhibitor, M33960 type I; Planh1 102663_at 0.00 0.00 0.00 5.528.24 0.00 PLAUR X62700 104580_at 0.00 0.00 0.00 0.00 13.32 9.79UNK_U85711 U85711 100607_at 0.00 0.00 6.30 10.02 22.31 16.77 Pld3AF026124 112083_at 0.00 3.60 4.03 3.29 3.72 4.57 PLEK AA389905 116483_at0.00 2.51 0.00 1.45 1.58 1.45 PLEK AA178053 93099_f_at 0.00 0.00 5.640.00 7.14 0.00 homolog, U01063 (Drosophila); Plk 101350_g_at 0.00 0.000.00 2.69 3.15 0.00 PLK-PS1 U73170 112304_at 0.00 0.00 0.00 2.53 2.403.41 PLOD1 AI854890 114376_at 0.00 0.00 0.00 10.32 19.49 16.29 PLOD2AW259579 95009_at 0.00 0.00 0.00 3.52 2.66 0.00 PLOD3 AW107836108848_g_at 0.00 2.15 2.34 3.50 3.60 3.50 UNK_AW261779 AW261779 93323_at0.00 1.77 1.99 4.35 4.15 3.14 UNK_AB031292 AB031292 94278_at 2.52 5.357.31 6.59 8.70 23.61 plastin 2, L; Pls2 D37837 102839_at 0.00 0.00 0.000.00 2.71 0.00 scramblase 1; D78354 Plscr1 100927_at 0.00 1.61 2.29 3.883.87 3.35 PLTP U28960 97900_at 0.00 0.00 0.00 2.38 0.00 0.00 PLUNCAI845714 93290_at 0.00 3.58 4.71 4.54 4.00 4.14 PNP U35374 103207_at0.00 0.00 0.00 1.97 2.15 1.44 POLA1 D13543 93940_at 0.00 0.00 0.00 0.002.74 2.18 Pon3 L76193 98508_s_at 0.00 0.00 0.00 2.11 1.67 1.47 PPAP2AD84376 109095_at 0.00 0.00 0.00 0.00 1.61 4.80 PPAP2C AI837099 101055_at0.00 0.00 0.00 1.90 2.19 4.26 beta-galactosidase; J05261 Ppgb 101207_at0.00 1.60 1.73 2.43 2.37 2.22 peptidylprolyl X52803 isomerase A; Ppia94915_at 0.00 2.15 2.53 4.59 5.13 5.64 PPIB X58990 100089_at 0.00 0.000.00 2.99 6.25 8.51 peptidylprolyl M74227 isomerase C; Ppic 97507_at0.00 1.87 3.36 5.70 2.90 4.09 isomerase C- X67809 associated protein;Ppicap 98993_at 0.00 2.04 0.00 3.07 3.11 3.12 protein phosphatase U594182, regulatory subunit B (B56), gamma isoform; Ppp2r5c 95631_at 0.00 1.741.72 2.71 2.96 2.24 UNK_AF088911 AF088911 93495_at 0.00 3.41 3.81 6.3310.88 6.68 Prdx4 U96746 95549_at 0.00 0.00 0.00 0.00 2.83 0.00 PRIM2D13545 100684_at 0.00 0.00 1.65 2.87 2.86 2.56 substrate 80K-H; U92794Prkcsh 102414_i_at 0.00 1.63 1.80 2.44 2.02 1.69 interferon inducibleU28423 double stranded RNA dependent inhibitor; Prkri 102415_r_at 0.000.00 0.00 0.00 2.50 0.00 interferon inducible U28423 double stranded RNAdependent inhibitor; Prkri 104728_at 0.00 2.54 0.00 3.40 4.10 4.80 Pros1L27439 103327_at 3.94 5.14 4.58 8.52 7.86 5.35 paired related X52875homeobox 2; Prrx2 93261_at 0.00 3.35 4.35 6.68 5.66 3.99 PRSC1 AJ00099096920_at 0.00 −1.76 0.00 0.00 3.99 3.39 PRSS11 AW125478 104102_at 0.000.00 0.00 0.00 5.09 0.00 UNK_AW047978 AW047978 103433_at 0.00 0.00 0.000.00 2.56 2.17 PSCD3 AI846077 102791_at 0.00 2.23 2.86 4.09 2.59 4.48PSMB8 U22033 100588_at 0.00 0.00 0.00 2.43 1.91 2.49 PSME2 U60329103946_at 0.00 3.04 0.00 5.29 5.18 14.26 threonine U87814 phosphatase-interacting protein 1; 102105_f_at 0.00 0.00 0.00 0.00 3.33 0.00 PTGDSAI840733 103362_at 0.00 1.42 0.00 1.93 3.68 0.00 receptor EP4 D13458subtype; Ptgerep4 104406_at 0.00 0.00 0.00 0.00 3.15 1.63 UNK_AI060798AI060798 104538_at 0.00 0.00 0.00 0.00 8.77 10.57 prostaglandin 12AB001607 (prostacyclin) synthase; Ptgis 104647_at 1.32 4.33 7.11 10.538.79 1.69 prostaglandin- M88242 endoperoxide synthase 2; Ptgs2 98482_at0.00 0.00 0.00 4.76 34.85 20.48 PTHR X78936 93646_at 0.00 1.74 0.00 0.004.58 2.84 PTK9 U82324 100718_at 0.00 2.16 2.29 3.42 3.73 4.16 PtmaX56135 96426_at 0.00 1.32 1.37 1.69 2.19 1.80 PTMB4 U38967 97474_r_at0.00 0.00 0.00 0.00 2.93 1.82 pleiotrophin; Ptn D90225 94929_at 0.002.13 0.00 2.61 2.81 4.92 PTPN1 M97590 98424_at 0.00 0.00 0.00 0.00 3.237.57 PTPN13 D83966 92273_at 1.97 3.65 0.00 3.39 0.00 0.00 PTPN18 U49853101996_at 0.00 1.60 0.00 0.00 2.29 1.61 PTPN2 M80739 100976_at 0.00 2.380.00 3.41 4.06 2.87 protein-tyrosine AF013490 phosphatase; Ptpn9103070_at 0.00 3.60 4.76 6.60 10.28 10.14 PTPNS1 AB018194 100908_at 0.000.00 0.00 2.22 6.03 10.00 phosphatase, M36033 receptor type, A; Ptpra101048_at 0.00 2.63 0.00 4.79 2.56 4.70 phosphatase, M14343 receptortype, C; Ptprc 101298_g_at 0.00 3.11 0.00 0.00 1.43 2.85 PTPRC M2315893896_at 0.00 0.00 0.00 0.00 5.11 6.76 phosphatase, D13903 receptortype, D; Ptprd 100427_at 0.00 2.56 2.33 2.28 1.23 2.61 phosphatase,U37465 receptor type, O; Ptpro 92731_at 3.07 17.44 6.55 6.96 5.75 0.00pentaxin related X83601 gene; Ptx3 96719_at 0.00 0.00 0.00 0.00 2.580.00 parvalbumin; Pva X59382 97415_at 0.00 0.00 0.00 0.00 3.23 4.63 RASoncogene M89777 family; Rab3d 103579_at 0.00 1.69 0.00 0.00 1.72 5.55RAS-related C3 X53247 botulinum substrate 2; Rac2 97319_at 0.00 3.343.30 9.39 11.41 5.14 UNK_AF084466 AF084466 96104_at 0.00 0.00 0.00 2.142.20 3.10 RAD23B AI047107 104527_at 0.00 0.00 2.19 2.89 2.79 0.00 RAD51D13803 93676_at 0.00 0.00 0.00 0.00 2.01 0.00 RAD51AP1 U93583102649_s_at 0.00 2.14 0.00 2.23 2.22 1.59 RAET1C D64162 106071_at 0.005.58 0.00 6.56 5.61 3.57 RALY AI852199 103299_at 1.92 0.00 2.97 3.914.13 3.15 UNK_AW123773 AW123773 114344_at 0.00 0.00 0.00 2.22 3.25 3.57UNK_AA882453 AA882453 101254_at 0.00 0.00 0.00 2.17 0.00 0.00 oncogenefamily; L32751 Ran 98573_r_at 0.00 2.30 2.42 3.53 2.49 2.60 RAN bindingprotein X56045 1; Ranbp1 93319_at 0.00 1.64 2.16 2.61 4.49 5.27 RAS p21protein U20238 activator 3; Rasa3 102821_s_at 0.00 0.00 0.00 2.31 0.000.00 RAS-like, family 2, L32752 locus 9; Rasl2-9 102379_at 0.00 3.372.64 3.54 0.00 0.00 UNK_AW049415 AW049415 104476_at 0.00 0.00 0.00 2.962.77 2.03 retinoblastoma-like 1 U27177 (p107); Rbl1 96041_at 0.00 2.152.72 3.76 2.78 2.42 RBM3 AB016424 97254_at 0.00 0.00 0.00 2.49 1.83 0.00UNK_AA690061 AA690061 94972_at 0.00 0.00 0.00 0.00 3.12 0.00UNK_AB026569 AB026569 97847_at 0.00 0.00 0.00 0.00 4.07 0.00 RBMXAJ237847 104716_at 0.00 0.00 0.00 3.52 4.52 2.49 protein 1, cellular;X60367 Rbp1 96047_at 0.00 0.00 0.00 0.00 3.29 3.03 protein 4, plasma;U63146 Rbp4 103804_at 0.00 0.00 0.00 0.00 3.42 2.10 ST15 AB006960102960_at 0.00 0.00 0.00 2.03 2.18 2.31 recombination X96618 activatinggene 1 gene activation; Rga 94378_at 0.00 0.00 0.00 0.00 3.49 0.00protein signaling 16; U94828 Rgs16 94899_at 0.00 0.00 0.00 0.00 2.082.09 protein 3; Rhoip3- U73200 pending 104094_at 0.00 0.00 0.00 0.002.15 0.00 LIM gene; Ril- Y08361 pending 114018_at 0.00 2.49 1.95 4.666.14 0.00 UNK_AI504675 AI504675 97091_at 0.00 0.00 0.00 0.00 3.11 2.05interacting serine- U25995 threonine kinase 1; Ripk1 96038_at 0.00 1.760.00 2.90 2.58 2.66 UNK_AI840339 AI840339 93164_at 0.00 0.00 0.00 0.002.18 2.16 ring finger protein 2; Y12783 Rnf2 93782_at 0.00 1.68 1.843.36 3.67 3.28 RNF4 AI844517 93453_at 0.00 0.00 0.00 0.00 2.62 0.00 rodouter segment M96760 membrane protein 1; Rom1 100711_at 0.00 0.00 0.002.10 1.93 0.00 ribosomal protein U12403 L10A; Rpl10a 92834_at 0.00 2.713.10 4.50 4.86 3.15 ribosomal protein X51528 L13a; Rpl13a 94208_at 0.002.29 3.47 4.81 4.93 2.77 RPL27A AW045202 94209_g_at 0.00 2.19 4.15 3.804.81 2.50 RPL27A AW045202 94207_at 0.00 2.31 2.67 4.56 2.55 0.00 RPL27AAI842377 95418_at 0.00 0.00 0.00 0.00 2.52 0.00 UNK_AI848851 AI848851100734_at 0.00 2.31 2.75 3.97 3.44 4.20 ribosomal protein Y00225 L3;Rpl3 108097_at 0.00 0.00 0.00 0.00 2.70 4.31 UNK_AW121237 AW12123799624_at 0.00 0.00 0.00 2.07 2.20 2.07 UNK_AW125517 AW125517 92325_at0.00 0.00 0.00 0.00 3.50 2.79 RPL7A AI326889 96295_at 0.00 2.06 2.944.52 9.84 5.38 RPMS7 AW122030 94076_i_at 0.00 1.53 1.91 3.06 2.69 2.95ribophorin; Rpn D31717 94077_f_at 0.00 0.00 0.00 2.44 2.46 2.44ribophorin; Rpn D31717 98081_at 0.00 0.00 0.00 2.75 3.10 2.31 RPO1-3AI853173 113001_at 0.00 0.00 0.00 2.04 1.65 0.00 RPS12 AI643492101922_at 0.00 1.67 1.76 4.37 4.88 4.01 RPS8 AW123408 100612_at 0.000.00 2.89 0.00 0.00 0.00 ribonucleotide K02927 reductase M1; Rrm1102001_at 0.00 4.09 4.93 4.37 4.89 2.47 ribonucleotide M14223 reductaseM2; Rrm2 101584_at 0.00 0.00 0.00 0.00 2.07 2.03 Ras suppressor X63039protein 1; Rsu1 92399_at 1.56 5.32 7.63 16.64 13.11 6.52 ranscriptionfactor D26532 1; Runx1 92676_at 0.00 1.60 2.51 4.67 13.58 14.15transcription factor D14636 2; Runx2 92539_at 0.00 2.45 2.84 3.90 5.124.18 protein A11 M16465 (calgizzarin); S100a10 98600_at 1.80 2.47 2.934.55 7.43 6.03 binding protein A11; U41341 S100a11 100959_at 0.00 1.560.00 2.63 2.65 2.69 binding protein A13; X99921 S100a13 100960_g_at 0.000.00 0.00 1.80 2.42 2.42 binding protein A13; X99921 S100a13 92770_at0.00 0.00 1.83 2.72 2.37 2.61 protein A6 X66449 (calcyclin); S100a695754_at 0.00 0.00 0.00 0.00 2.08 2.47 UNK_AI838216 AI838216 102712_at−3.84 2.96 4.98 8.61 4.23 0.00 Saa3 X03505 102012_at 0.00 3.45 2.78 6.044.14 5.35 SAPS AB014485 97340_at 0.00 0.00 0.00 0.00 9.89 4.81 SART3AI839599 96657_at 0.00 0.00 2.35 3.95 3.54 3.47 N1-acetyl L10244transferase; Sat 99127_at 0.00 0.00 0.00 2.14 2.18 2.16 ataxia 10homolog X61506 (human); Sca10 95758_at 0.00 0.00 1.71 3.17 5.87 3.76 Adesaturase 2; M26270 Scd2 103244_at 0.00 2.16 1.90 6.42 14.12 8.60 SCGFAB009245 101132_at 0.00 0.00 0.00 0.00 2.13 0.00 voltage-gated, typeL36179 VI, alpha polypeptide; Scn6a 92755_f_at 0.00 0.00 0.00 3.02 0.000.00 secretin; Sct X73580 94140_at 0.48 2.44 −2.79 0.00 0.00 0.00 SCVRM59446 93717_at 2.82 3.56 −0.43 1.69 2.72 −0.33 cytokine A12; U50712Scya12 102736_at 2.71 5.21 6.15 9.01 7.67 2.10 small inducible M19681cytokine A2; Scya2 92849_at 2.26 2.31 0.00 0.00 0.00 0.00 smallinducible M58004 cytokine A6; Scya6 94761_at 3.20 6.30 7.57 6.75 7.080.00 SCYA7 X70058 104388_at 2.37 2.97 2.84 3.61 2.34 5.38 SCYA9 U4951393858_at 0.00 0.00 4.64 3.50 1.42 1.46 cytokine B subfamily M33266(Cys-X-Cys), member 10; Scyb10 96953_at 0.00 3.54 0.00 2.92 2.95 0.00KEC AW120786 98772_at 3.38 5.10 0.00 2.26 0.00 0.00 cytokine B U27267subfamily, member 5; Scyb5 98008_at 0.00 0.00 0.00 0.00 5.32 0.00cytokine subfamily U92565 D, 1; Scyd1 96033_at 0.00 0.00 0.00 0.00 3.393.96 syndecan 1; Sdc1 Z22532 95104_at 0.00 0.00 0.00 0.00 7.78 5.08syndecan 2; Sdc2 U00674 98590_at 0.00 1.50 0.00 0.00 5.17 2.08 syndecan4; Sdc4 D89571 93017_at 0.00 2.05 2.50 2.98 2.03 2.97 SDCBP AF077527110314_at 0.00 0.00 0.00 3.88 0.00 0.00 UNK_AA939505 AA939505 93503_at3.23 2.68 3.83 5.83 5.65 6.03 SDF5 U88567 103421_at 0.00 0.00 0.00 2.752.23 4.03 factor receptor 2; D50464 Sdfr2 102319_at 0.00 0.00 0.00 0.002.38 0.00 SDP8 AF062484 110816_at 0.00 1.86 2.60 3.96 4.31 4.31 SEC22L1AI836222 103953_at 0.00 0.00 0.00 4.26 4.62 2.88 trafficking protein-U91538 like 1 (S. cerevisiae); Sec22l1 93711_at 0.00 0.00 0.00 0.00 2.090.00 SEC23A (S. D12713 cerevisiae); Sec23a 98944_at 0.00 2.50 3.56 6.123.76 3.03 UNK_AI848343 AI848343 97882_at 0.00 2.61 2.86 6.48 9.11 5.92SEC61A AB032902 92870_at 0.00 0.00 0.00 2.77 0.00 0.00 SEL1H AF063095100457_at 0.00 0.00 0.00 2.17 2.21 2.29 selectin, endothelial X84037cell, ligand; Selel 104692_at 0.00 2.30 0.00 0.00 0.00 0.00 SELP M7233294063_at 0.00 0.00 0.00 0.00 4.29 0.00 immunoglobulin X85991 domain(Ig), transmembrane domain (TM) and short cytoplasmic domain,(semaphorin) 4A; 103094_at 0.00 0.00 0.00 0.00 5.61 4.54 SERF1 AI036894102641_at 0.00 7.13 3.23 5.34 3.39 11.03 SFPI1 L03215 97997_at 0.00 4.246.40 9.69 9.18 2.33 secreted frizzled- U88566 related sequence protein1; Sfrp1 104672_at 0.00 0.00 0.00 0.00 12.10 0.00 secreted frizzled-U68058 related sequence protein 3; Sfrp3 95791_s_at 0.00 0.00 0.00 2.662.33 0.00 arginine/serine-rich U14648 10, splidng factor,arginine/serine-rich 2 (SC-35); Sfrs10, Sfrs2 94017_s_at 0.00 0.00 0.002.08 0.00 0.00 SFRS2 X98511 101004_f_at 0.00 2.16 2.00 2.68 2.36 2.18splicing factor, X91656 arginine/serine-rich 3 (SRp20); Sfrs3 101861_at0.00 0.00 0.00 0.00 2.24 2.47 SGCE AF031919 96127_at 0.00 2.31 2.89 3.473.36 6.40 SGPL1 AW048730 93806_at 0.00 2.17 2.28 2.89 3.44 5.41UNK_AI848671 AI848671 92975_at 0.00 2.44 2.15 2.25 2.45 3.07 SH3-domainbinding L14543 protein 2; Sh3bp2 103755_at 0.00 0.00 0.00 2.54 5.91 3.28SH3 domain protein D89677 D19; Sh3d19 93275_at 0.00 0.50 0.00 2.58 5.004.00 SH3 domain protein U58885 2B; Sh3d2b 99158_at 0.00 1.76 1.70 3.102.59 2.16 SH3 domain protein U58888 3; Sh3d3 95456_r_at 0.00 0.00 0.000.00 2.03 1.83 deleted gene 1; U41626 Shfdg1 99042_s_at 0.00 0.00 0.002.57 4.04 6.81 SHOX2 U66918 102752_at 0.00 2.08 2.08 3.26 1.98 2.62 SHYCAF072697 94432_at 0.00 0.00 0.00 0.00 2.68 3.64 UNK_AI117157 AI11715799847_at 0.00 0.00 0.00 0.00 3.29 3.93 Siat4 X73523 95599_at 0.00 0.000.00 0.00 4.82 3.35 sialyltransferase 4c; D28941 Siat4c 94492_at 0.000.00 0.00 2.96 3.59 4.98 UNK_AB025406 AB025406 99655_at 0.00 0.00 0.002.64 2.61 2.30 UNK_AB025405 AB025405 95144_at 0.00 0.00 0.00 2.28 1.751.94 UNK_AB024984 AB024984 97489_at 0.00 0.00 0.00 0.00 2.58 3.90UNK_AI846739 AI846739 93789_s_at 0.00 1.63 0.00 2.55 3.08 3.28 SIN3BAF038848 92450_at 0.00 0.00 0.00 0.00 2.37 2.54 SLC12A4 AF047339104719_at 0.00 2.21 0.00 0.00 3.05 2.14 SLC12A7 AI182203 100491_at 0.000.00 0.00 1.90 2.76 0.00 SLC16A2 AF045692 100943_at 0.00 0.00 0.00 7.007.27 2.37 neutral amino acid U75215 transporter; Slc1a4 103065_at 0.001.93 0.00 4.69 6.26 3.25 20, member 1; M73696 Slc20a1 99112_at 0.00 0.000.00 0.00 1.63 3.71 SLC25A10 AA683883 97473_at 0.00 8.03 4.82 19.2314.32 7.15 SLC25A17 AW124470 97472_at 0.00 0.00 0.00 2.35 2.52 0.00SLC25A17 AJ006341 100618_f_at 0.00 0.00 0.00 5.23 4.78 7.59 25(mitochondrial AA062013 carrier; adenine nucleotide translocator),member 5; Slc25a5 97957_at 0.00 0.00 0.00 0.00 2.19 0.00 SLC27A4AF072759 95733_at 0.00 0.00 0.00 0.00 3.22 3.31 UNK_AI838274 AI83827495571_at 0.00 0.00 0.00 0.00 1.83 2.40 SLC30A4 AF004100 101877_at 0.001.78 1.74 2.74 3.70 3.40 SLC31A1 AI854432 103845_at 0.00 0.00 0.00 2.782.72 0.00 UNK_AI839005 AI839005 93558_at 0.00 0.00 0.00 2.33 3.66 2.36SLC35A2 AB027147 100020_at 0.00 0.00 0.00 0.00 3.18 6.84 solute carrierfamily J04036 4 (anion exchanger), member 2; Slc4a2 103818_at 0.00 3.940.00 0.00 7.66 4.45 SLC7A7 AJ012754 104214_at 0.00 2.48 0.00 0.00 0.000.00 SLC7A8 AW122706 99524_at 0.00 0.00 0.00 2.03 0.00 0.00 solutecarrier family AF004666 8 (sodium/calcium exchanger), member 1; Slc8a1102264_at 2.09 0.00 2.47 2.09 1.99 2.48 SLFN1 AF099972 92472_f_at 2.333.93 4.37 4.87 3.05 3.83 SLFN2 AF099973 92471_i_at 0.00 3.71 3.39 5.908.39 4.15 SLFN2 AF099973 92858_at 0.00 4.23 2.55 6.22 7.43 3.89 SLPIAF002719 99552_at 3.78 17.54 20.88 10.28 11.85 25.49 slug, chickenU79550 homolog; Slugh 96050_at 0.00 0.00 0.00 7.04 4.66 0.00 SMARCB1AJ011740 102062_at 0.00 0.00 4.08 0.00 4.73 3.19 matrix associated,U85614 actin dependent regulator of chromatin, subfamily c, member 1;106277_at 0.00 0.00 0.00 2.18 2.30 3.29 UNK_AW120530 AW120530 96812_at0.00 0.00 0.00 2.57 6.03 2.71 SMOH AF089721 103830_at 0.00 2.85 0.000.00 3.62 1.44 snail homolog, M95604 Drosophila); Sna 101530_at 0.000.00 0.00 2.32 2.60 1.69 ribonucleoprotein U97079 116 kDa; Snrp116-pending 101506_at 0.00 0.00 0.00 2.55 0.00 0.00 UNK_AW227345 AW227345100577_at 0.00 0.00 2.41 0.00 2.31 2.11 small nuclear M58558ribonucleoprotein D1; Snrpd1 112282_s_at 0.00 3.18 4.02 4.54 4.18 4.52UNK_AI154073 AH 54073 112283_at 1.68 2.68 0.00 3.14 7.08 5.94UNK_AA718584 AA718584 94550_at 0.00 2.19 1.41 1.85 1.56 2.92UNK_AW121324 AW121324 94902_at 0.00 1.87 0.00 2.17 2.23 1.87 dismutase3, U38261 extracellular; Sod3 111853_at 0.00 0.00 0.00 1.50 4.58 3.78SOUL-PENDING AA726177 104408_s_at 0.00 0.00 0.00 0.00 2.29 2.61 SRY-boxcontaining L35032 gene 18; Sox18 101430_at 0.00 0.00 0.00 2.09 4.36 6.01SOX4 AW124153 100032_at 0.00 0.00 0.00 2.03 2.18 0.00 transcriptionfactor X60136 1; Sp1 113152_at 0.00 0.00 0.00 1.99 2.66 0.00SPAK-PENDING AI850672 97160_at 0.00 0.00 0.00 3.53 3.24 3.71 cysteinerich X04017 glycoprotein; Sparc 97817_at 0.00 1.94 1.93 3.63 3.06 3.46UNK_AW121136 AW121136 104374_at 0.00 5.69 5.43 8.11 4.63 0.00 serineprotease M64086 inhibitor 2-2; Spi2-2 96060_at 0.00 0.00 0.00 2.21 1.731.92 serine protease U25844 inhibitor 3; Spi3 97487_at 0.00 0.00 0.000.00 2.61 6.46 serine protease X70296 inhibitor 4; Spi4 98405_at 0.000.00 0.00 0.00 5.15 0.00 serine protease U96700 inhibitor 6; Spi6102125_f_at 0.00 0.00 1.30 0.00 2.11 0.00 SPI6 AI838923 99528_at 0.000.00 0.00 0.00 1.58 2.19 SPIN AW122015 99563_at 0.00 0.00 0.00 0.00 1.952.49 SPIN AW124681 97519_at 2.00 2.60 5.99 14.15 24.33 29.32 SPP1 X1398694322_at 0.00 2.38 2.44 0.00 3.97 0.56 squalene epoxidase; D42048 Sqle100095_at 0.00 0.00 0.00 1.76 1.71 2.24 scavenger receptor U37799 classB1; Srb1 96712_at 0.00 0.00 0.00 5.45 0.00 0.00 UNK_AI848508 AI84850892540_f_at 0.00 2.10 2.30 7.95 5.95 3.58 SRM Z67748 103568_at 0.00 2.434.42 4.07 17.64 6.56 SRPX-PENDING AB028049 92265_f_at 0.00 0.00 0.000.00 1.91 3.63 SSA2 AF042139 99610_at 0.00 0.00 0.00 0.00 1.96 2.34synovial sarcoma, X93357 translocated to X chromosome; Ssxt 101465_at0.00 0.00 0.00 3.32 2.28 4.66 signal transducer U06924 and activator oftranscription 1; Stat1 115806_at 0.00 0.00 3.13 2.81 0.00 0.00UNK_AI851966 AI851966 99100_at 0.00 0.00 0.00 0.00 2.73 0.00 STATSAI837104 94331_at 0.00 2.04 0.00 0.00 2.15 2.15 signal transducer L47650and activator of transcription 6; Stat6 93272_at 0.00 0.00 0.00 0.002.30 2.62 STK16 AF062076 98996_at 0.00 2.59 2.69 3.64 4.59 2.59 STK18L29480 92639_at 0.00 1.93 0.00 2.47 2.35 0.00 serine/threonine U80932kinase 6; Stk6 96076_at 0.00 0.00 0.00 2.18 3.12 2.49 UNK_AW121716AW121716 99146_at 0.00 0.00 0.00 1.89 3.17 3.15 UNK_AW124355 AW12435597983_s_at 0.00 0.00 0.00 0.00 2.13 0.00 syntaxin binding D45903 protein1; Stxbp1 95703_at 0.00 0.00 0.00 3.28 1.98 1.70 UNK_AB024303 AB024303101901_at 0.00 0.00 2.31 2.55 1.48 1.72 SUPL15H AB024713 96542_at 0.000.00 0.00 0.00 4.43 4.05 surfeit gene 4; Surf4 M62606 97238_at 0.00 1.752.05 1.79 1.87 0.00 TACC3 AW209238 93541_at 0.00 0.00 0.00 2.16 3.730.00 TAGLN Z68618 93333_at 0.00 0.00 2.00 2.33 2.00 2.02 Tbca U0533398937_at 0.00 0.00 1.55 3.06 3.36 2.94 TBRG1 AW049795 104655_at 0.000.00 0.00 0.00 1.42 2.13 UNK_AA755817 AA755817 97994_at 0.00 0.00 0.000.00 8.61 7.06 TCF7 AI019193 97995_at 0.00 0.00 0.00 0.00 2.94 2.18 7,T-cell specific; X61385 Tcf7 97901_at 0.00 0.00 0.00 0.00 3.66 0.00transcription factor X60831 UBF; Tcfubf 93736_at 0.00 0.00 0.00 0.001.97 3.23 TCN2 AF090686 101540_at 0.00 0.00 0.00 1.89 2.12 1.40 TDGAF069519 108581_at 0.00 0.00 0.00 0.00 2.46 4.50 UNK_AI835817 AI835817116324_g_at 0.00 0.00 0.00 0.00 1.48 2.45 TEDP2-PENDING AI85189393367_at 0.00 0.00 0.00 2.20 3.14 3.08 associated protein 1; U86137 Tep1103385_at 0.00 0.00 0.00 1.97 2.16 1.87 teratocarcinoma U64033expressed, serine rich; Tera 99138_at 0.00 2.50 0.00 2.37 2.41 2.06 TFGAA756292 98514_at 0.00 0.00 0.00 3.17 4.49 2.87 TFPI AF004833 94383_at0.00 0.00 0.00 4.72 5.97 5.52 pathway inhibitor 2; D50586 Tfpi2101918_at 0.00 0.00 0.00 0.00 11.46 8.03 TGFB1 AJ009862 98019_at 0.000.00 0.00 0.00 8.41 3.84 factor beta 1 L22482 induced transcript 1;Tgfb1i1 93728_at 0.00 2.12 2.20 3.09 3.15 2.65 factor beta 1 X62940induced transcript 4; Tgfb1i4 93300_at 0.00 0.00 0.00 0.00 3.26 0.00transforming growth X57413 factor, beta 2; Tgfb2 102751_at 0.00 0.000.00 3.15 3.21 1.80 transforming growth M32745 factor, beta 3; Tgfb392877_at 2.66 4.57 4.66 7.44 3.85 2.47 transforming growth L19932factor, beta induced, 68 kDa; Tgfbi 101502_at 0.00 0.00 2.62 4.72 4.013.84 TG interacting X89749 factor; Tgif 104601_at 0.00 2.79 0.00 0.002.21 0.00 Thbd X14432 94930_at 0.00 0.00 0.00 6.81 11.52 6.37 Thbs2L07803 103869_at 0.00 0.00 4.33 17.37 14.36 8.82 protein, mucin 1,U16175 transmembrane, throm- bospondin 3; LOC54129, Muc1, Thbs3 99057_at0.00 1.45 0.00 2.57 3.87 1.98 THY1 M12379 93071_at 0.00 0.00 0.00 2.372.57 1.98 TIF1B X99644 93507_at 0.00 0.00 0.00 0.00 3.00 3.30 tissueinhibitor of X62622 metalloproteinase 2; Timp2 103671_at 0.00 0.00 0.000.00 3.68 2.01 TIP30-PENDING AF061972 102273_at 0.00 0.00 0.00 1.73 2.461.93 TJ6 M31226 99935_at 0.00 0.00 0.00 0.00 2.21 2.70 tight junctionprotein D14340 1; Tjp1 96081_at 0.00 0.00 0.67 0.00 8.09 0.00 TK1 X60980110423_at 0.00 0.00 0.00 0.00 6.50 2.22 UNK_AA895554 AA895554 104623_at0.00 0.00 0.00 0.00 2.35 3.25 enhancer of split 3, X73360 homolog ofDrosophila E(spl); 98304_at 0.00 1.55 0.00 2.11 1.46 1.57 TLR6 AB02080892555_at 0.00 0.00 2.39 3.84 11.52 5.85 UNK_AF053454 AF053454 100039_at0.00 0.00 0.00 2.65 5.36 3.33 UNK_AW125880 AW125880 115179_at 0.00 2.540.00 0.00 0.00 0.00 UNK_AA718842 AA718842 99013_f_at 0.00 1.67 0.00 2.363.05 3.11 TMOD3 AI846797 115913_at 0.00 0.00 0.00 2.69 4.01 3.29 TMOD3AI526875 101993_at 0.00 3.87 7.79 16.34 19.51 19.59 tenascin C; TncX56304 98474_r_at 0.00 1.62 2.24 1.98 1.85 2.10 factor induced U83903protein 6; Tnfip6 102887_at 0.00 0.00 0.00 0.00 10.64 3.70 OPG U9433192793_at 0.00 3.30 0.00 2.34 3.22 2.94 TNFRSF1A X57796 94928_at 0.001.58 2.10 2.39 1.72 3.94 TNFRSF1B X87128 93416_at 0.00 1.93 1.50 0.002.12 4.02 factor (ligand) AF019048 superfamily, member 11; Tnfsf 11100593_at 0.00 0.00 0.00 0.00 12.73 3.78 TNNT2 L47600 99578_at 0.00 1.983.26 3.07 3.45 1.98 TOP2A U01915 95505_at 0.00 0.00 0.00 2.60 0.00 0.00TOR1B AW060509 97557_at 0.00 0.00 0.00 0.00 3.90 0.00 TOR2A AI84145795345_at 0.00 0.00 0.00 1.80 3.25 2.14 TPBG AJ012160 103032_at 0.00 0.000.00 0.00 2.37 2.26 TPST1 AF038008 94948_at 0.00 0.00 0.00 0.00 4.954.19 TRIP6 AF097511 104154_at 0.00 2.21 0.00 0.00 4.07 0.00 TRP53AB021961 104275_g_at 0.00 0.00 0.00 0.00 2.73 0.00 TRP53 AB02196196183_at 0.00 0.00 2.23 0.00 2.20 2.47 UNK_AW122985 AW122985 93538_at0.00 0.00 0.00 2.02 0.00 0.00 TTRAP-PENDING AW228036 100342_i_at 0.002.12 2.24 4.45 5.18 2.86 TUBA1 M28729 100343_f_at 0.00 1.98 2.03 3.132.91 2.34 TUBA1 M28729 98759_f_at 0.00 2.05 1.98 3.16 3.39 2.73 TUBA2M28727 101543_f_at 0.00 2.06 2.24 3.40 3.14 2.65 TUBA6 M13441 94835_f_at0.00 2.92 2.73 4.98 5.58 3.49 Tubb2 M28739 94788_f_at 0.00 3.11 3.625.63 6.28 4.29 Tubb5 X04663 94789_r_at 0.00 7.98 8.12 78.06 13.75 7.31TubbS X04663 98028_at 0.00 0.00 1.73 1.28 5.13 7.55 TWIST M6364992807_at 0.00 1.60 2.05 2.73 2.29 2.42 TXN X77585 93237_s_at 0.00 1.820.00 0.00 4.28 3.89 TYMS AU044050 100397_at 2.04 3.39 3.70 5.63 5.0012.41 TYROBP AF024637 97304_at 0.00 0.00 0.00 0.00 2.07 2.44 UBP1AI836100 98972_at 0.00 0.00 0.00 0.00 5.36 2.56 UNK_AI574262 AI57426294197_at 0.00 3.03 0.00 2.40 3.38 0.00 UGCG D89866 102322_at 2.51 2.382.67 3.94 4.24 4.11 UGDH AF061017 95024_at 1.90 0.00 3.20 3.26 2.42 0.00USP18 AW047653 93305_f_at 0.00 0.00 5.69 4.47 3.95 3.50 VAMP8 AF053724100345_f_at 0.00 0.00 0.00 2.62 2.67 2.60 VAMP8 W65964 101982_at 0.001.36 0.00 2.45 2.66 2.27 stimulated X98475 phosphoprotein; 99799_at 1.443.13 0.00 2.64 2.99 2.40 vav oncogene; Vav X64361 96511_s_at 0.00 0.000.00 0.00 2.07 0.00 vav oncogene; Vav D83266 95490_at 0.00 0.00 0.002.26 3.00 2.09 UNK_AW120891 AW120891 92558_at 0.00 3.13 0.00 4.11 5.4911.07 VCAM1 M84487 92559_at 1.22 1.55 0.00 0.00 2.01 2.67 VCAM1 U1288492560_g_at 0.00 0.00 0.00 0.00 3.35 4.56 VCAM1 U12884 100084_at 0.000.00 0.00 0.00 2.73 3.56 villin 2; Vil2 X60671 101047_at 0.00 0.00 0.000.00 2.12 1.73 VIM AW123697 93337_at 0.00 0.00 0.00 2.13 1.83 2.11sorting 4b (yeast); U10119 Vps4b 98963_at 0.00 2.85 0.00 0.00 4.71 3.54VRL1 AB021665 100522_s_at 0.00 0.00 0.00 3.20 3.75 3.21 WW domainbinding U92454 protein 5; Wbp5 100523_r_at 0.00 0.00 0.00 2.41 3.13 2.02WW domain binding U92454 protein 5; Wbp5 103690_at 0.00 3.29 2.41 5.123.55 5.88 UNK_AW125574 AW125574 96075_at 0.00 2.11 0.00 3.70 2.89 3.37WDR1 AW060876 92262_at 0.00 0.00 0.00 0.00 3.19 0.00 WIG1 AF012923102044_at 0.00 2.42 3.42 11.06 23.81 19.33 ELM1 AF100777 102891_at 0.000.00 0.00 1.63 2.46 2.59 WRN D86527 113110_at 0.00 0.00 0.00 0.00 2.423.11 WRN AA960405 98946_at 0.00 1.87 0.00 4.72 3.95 3.55 UNK_AF033186AF033186 113094_at 0.00 0.00 0.00 0.00 3.83 0.00 UNK_AA175692 AA175692100958_at 0.00 0.00 0.00 0.00 4.56 7.64 UNK_AI647003 AI647003 99126_at0.00 0.00 0.00 0.00 2.03 3.61 inactive X specific L04961 transcripts;Xist 92665_f_at 0.00 0.00 0.00 0.00 1.94 2.01 regulated complex; X07967Xlr 100015_at 0.00 0.00 0.00 0.00 2.30 0.00 viral (v-yes) X67677oncogene homolog; Yes 104400_at 0.00 2.18 0.00 2.06 3.18 2.96UNK_AF076956 AF076956 97229_at 0.00 0.00 0.00 2.05 0.00 0.00UNK_AW061042 AW061042 97535_at 0.00 1.63 2.14 2.89 2.41 2.21monooxygenase/tryp- D87661 tophan 5- monooxygenase activation protein,eta polypeptide; 97061_g_at 0.00 1.94 2.17 2.75 3.19 3.36 YWHAQ AW21548997544_at 0.00 1.72 0.00 2.31 3.14 2.92 YWHAZ D83037 92501_s_at 0.00 0.000.00 0.00 5.24 4.39 ZAC1 X95503 92502_at 0.00 0.00 0.00 1.40 7.40 6.62ZAC1 X95504 100475_at 0.00 0.00 0.00 3.36 2.20 2.88 zinc finger proteinD63902 147; Zfp147 92771_at 0.00 0.00 0.00 0.00 2.13 1.97 ZFP207AB013357 102277_at 0.00 0.00 0.00 0.00 2.59 0.00 ZFP26 M36514 92934_at0.00 0.00 0.00 0.00 2.66 0.00 zinc finger protein X79828 90; Zfp90103676_at 0.00 0.00 0.00 0.00 2.06 2.03 UNK_AI551306 AI551306

[0359] TABLE 2 Treatment BMP2 BMP2 BMP2 BMP2 BMP2 BMP2 Time day 01 day02 day 03 day 04 day 07 day 14 Affymetrix Avg. Fold Avg. Fold Avg. FoldAvg. Fold Avg. Fold Avg. Fold Genbank Qualifier Change Change ChangeChange Change Change Gene Name Accession # 115844_at −2.74 −4.65 −3.15−2.76 −2.12 −2.10 UNK_AI847028 AI847028 103494_at 0.00 −2.50 −3.42 −2.87−4.24 −2.99 UNK_AI047972 AI047972 104342_i_at 0.00 −4.22 −3.45 −5.08−10.18 −4.00 UNK_AI845798 AI845798 107074_at 0.00 −2.55 −2.53 −3.42−4.39 −2.24 UNK_AI838083 AI838083 133738_at 0.00 −2.30 −2.02 −3.17 −4.39−3.23 UNK_AI467229 AI467229 133932_at 0.00 −2.17 −2.06 −3.16 −4.05 −2.76UNK_AI503993 AI503993 133951_at 0.00 −3.22 −3.10 −10.36 −6.86 −2.39UNK_AI504979 AI504979 94534_at 0.00 −2.04 −2.11 0.00 −4.07 −2.36UNK_AI835446 AI835446 94790_at 0.00 −2.24 −2.48 0.00 −3.80 −2.57UNK_AA681807 AA681807 95468_at 0.00 −2.15 −1.91 −2.63 −4.12 −2.55 BTDAI850202 96391_at 0.00 −2.96 −2.60 −1.90 −3.00 −2.41 EST; unknown C80836105638_at 0.00 −3.95 −4.59 0.00 −10.36 −2.07 UNK_AA896641 AA896641106963_at 0.00 −2.48 −2.10 0.00 −3.26 −3.68 UNK_AW050323 AW050323107282_at 0.00 −2.07 −2.27 0.00 −4.69 −4.22 UNK_AW047933 AW047933107418_at 0.00 −2.16 0.00 −3.07 −5.71 −2.08 UNK_AW046245 AW046245107952_i_at 0.00 −2.62 −2.43 0.00 −2.93 −2.12 UNK_AA606601 AA606601109968_at 0.00 −5.91 −3.57 0.00 −8.76 −2.67 UNK_AA771415 AA771415110269_at −2.16 −5.45 −2.93 0.00 −3.03 0.00 UNK_AW045975 AW045975115109_at 0.00 −2.05 −1.79 −4.17 −4.31 −2.28 UNK_AI838503 AI838503115246_at 0.00 −1.95 −2.61 −3.31 −5.64 −2.62 UNK_AA790442 AA790442116614_at 0.00 −2.54 −2.37 0.00 −3.72 −2.01 UNK_AA647405 AA647405129661_at 0.00 −2.57 −3.45 0.00 −3.41 −2.12 UNK_AA792999 AA792999130718_at 0.00 −2.98 −2.27 0.00 −2.50 −2.32 UNK_AI844247 AI844247133977_at 0.00 −3.33 −2.14 −3.11 −2.79 −1.68 UNK_AI506633 AI506633135609_at 0.00 −2.66 0.00 −2.42 −4.25 −2.42 UNK_AI505553 AI50555393514_at 0.00 −2.76 −1.94 0.00 −4.77 −5.23 MYLC X12972 94418_at 0.00−2.71 −8.42 0.00 −2.51 −0.63 UNK_AI839004 AI839004 94908_r_at 0.00 0.00−2.19 0.00 −4.76 −2.57 UNK_AW045632 AW045632 95587_at 0.00 −2.33 −2.230.00 −2.97 −1.80 UNK_AI837204 AI837204 98942_r_at 0.00 −2.33 −3.05 0.00−3.93 −1.78 UNK_AW125284 AW125284 102862_at 0.00 0.00 −3.42 0.00 −3.42−3.17 UNK_AA873956 AA873956 102916_s_at 0.00 −4.25 −3.83 0.00 −2.86 0.00UNK_AB010266 AB010266 102922_at 0.00 −3.08 −2.52 0.00 −2.84 −1.50UNK_AI851387 AI851387 105610_at 0.00 0.00 −2.89 0.00 −4.34 −2.22UNK_AA388982 AA388982 106934_at 0.00 0.00 −2.79 0.00 −10.65 −4.94UNK_AW047806 AW047806 107569_at 0.00 −2.01 0.00 0.00 −2.37 −2.03UNK_AA738625 AA738625 110774_at 0.00 −3.03 −2.48 0.00 −2.45 −1.51UNK_AI852667 AI852667 111228_at 0.00 −1.68 −2.69 0.00 −2.72 −2.01UNK_AW122874 AW122874 111254_at 0.00 −2.06 −2.12 0.00 −3.40 −1.69UNK_AA735016 AA735016 111260_at 0.00 0.00 −2.66 0.00 −3.27 −3.11UNK_AI843809 AI843809 112012_at 0.00 −2.13 −2.12 0.00 −4.16 −1.67UNK_AI875092 AI875092 113124_at 0.00 −4.08 0.00 0.00 −8.64 −2.40UNK_AI852911 AI852911 113806_at 0.00 0.00 −2.69 0.00 −2.68 −2.20UNK_AW121611 AW121611 114138_at 0.00 0.00 −2.00 0.00 −5.82 −2.95UNK_AI643851 AI643851 114297_f_at 0.00 −1.96 −2.03 0.00 −4.33 −2.31UNK_AI021087 AI021087 114466_at 0.00 −1.89 −2.07 0.00 −3.21 −2.18UNK_AA197511 AA197511 116583_at 0.00 −2.08 −1.70 0.00 −3.36 −2.23UNK_AW121389 AW121389 116792_at 0.00 −1.94 −3.96 0.00 −4.51 −3.31UNK_AI480742 AI480742 129309_at 0.00 −2.55 −1.92 0.00 −3.86 −2.58UNK_AI596885 AI596885 129952_at 0.00 0.00 −2.17 0.00 −2.85 −2.68UNK_AI595378 AI595378 135181_f_at 0.00 −1.74 −1.70 −2.21 −3.48 −2.24UNK_AW125817 AW125817 139035_at 0.00 −2.05 0.00 −2.09 −2.40 0.00UNK_AI846518 AI846518 140572_at 0.00 −2.94 −2.45 0.00 −2.88 0.00UNK_AW125201 AW125201 92202_g_at 0.00 0.00 0.00 0.00 −3.21 −2.40UNK_AI553024 AI553024 92941_at 0.00 0.00 0.00 0.00 −3.70 −2.71UNK_AA833509 AA833509 93177_at 0.00 0.00 0.00 0.00 −3.03 −2.08UNK_AW121661 AW121661 93780_at 0.00 −2.35 −1.92 0.00 −2.37 −1.95UNK_AW060827 AW060827 95376_at 0.00 0.00 0.00 0.00 −5.44 −5.10UNK_AJ011107 AJ011107 95518_at 0.00 −2.12 −1.76 0.00 −2.06 0.00UNK_AW122893 AW122893 96211_at 0.00 0.00 0.00 −2.61 −4.19 0.00UNK_AI846896 AI846896 99331_at 0.00 0.00 0.00 0.00 −3.02 −4.46UNK_AW125581 AW125581 99503_at 0.00 −2.49 0.00 0.00 −2.85 −1.74UNK_AW045204 AW045204 100058_at 0.00 0.00 0.00 0.00 −2.34 −3.75UNK_AW047776 AW047776 103257_at 0.00 0.00 −1.75 0.00 −2.96 −2.37UNK_AA690483 AA690483 103665_at 0.00 −2.26 −5.60 0.00 −1.79 −0.73UNK_AW122523 AW122523 104153_at 0.00 0.00 0.00 0.00 −3.18 −2.04UNK_AW047743 AW047743 104293_at 0.00 0.00 −1.95 0.00 −2.61 −2.73UNK_AI882440 AI882440 104445_at −1.69 −3.53 −2.56 0.00 −1.65 0.00UNK_AW046694 AW046694 104491_at 0.00 −1.77 −2.21 0.00 −2.08 0.00UNK_AI509330 AI509330 104804_at 0.00 −1.61 0.00 0.00 −2.94 −2.31UNK_AI504570 AI504570 104944_at 0.00 0.00 0.00 0.00 −2.25 −2.14UNK_AA619815 AA619815 105168_at 0.00 −1.76 0.00 0.00 −2.67 −2.61UNK_AI847519 AI847519 105569_at 0.00 0.00 −1.98 0.00 −3.12 −3.32UNK_AI605044 AI605044 105619_at 0.00 0.00 0.00 0.00 −20.58 −7.69UNK_AI849242 AI849242 105706_at 0.00 0.00 0.00 0.00 −3.77 −2.26UNK_AI847342 AI847342 106065_at 0.00 −2.29 0.00 0.00 −2.40 0.00UNK_AI849096 AI849096 106297_at 0.00 −2.02 0.00 0.00 −2.32 0.00UNK_AI841521 AI841521 106439_at 0.00 0.00 0.00 0.00 −3.25 −3.88UNK_AI851838 AI851838 106505_at 0.00 −1.79 0.00 0.00 −2.85 −2.52UNK_AI844271 AI844271 106521_at 0.00 −2.23 0.00 0.00 −4.38 0.00UNK_AI987764 AI987764 106896_at 0.00 0.00 0.00 0.00 −2.96 −2.16UNK_AW049892 AW049892 107400_at 0.00 −2.00 −2.22 0.00 −1.83 0.00UNK_AW048204 AW048204 107427_at 0.00 −1.59 0.00 0.00 −3.02 −2.22UNK_AW122504 AW122504 107428_at 0.00 0.00 0.00 0.00 −2.66 −2.13UNK_AW046414 AW046414 108010_at 0.00 0.00 0.00 0.00 −3.82 −2.72UNK_AW210455 AW210455 108069_at 0.00 0.00 0.00 0.00 −2.51 −2.13UNK_AI642606 AI642606 108488_at 0.00 0.00 0.00 0.00 −2.80 −2.49UNK_AI838112 AI838112 108565_at 0.00 −2.68 −2.95 0.00 2.66 4.55UNK_AI853095 AI853095 108767_at 0.00 −2.42 0.00 0.00 −3.47 0.00UNK_AI448797 AI448797 108822_at 0.00 0.00 0.00 −3.70 −3.72 0.00UNK_AI615758 AI615758 109049_at 0.00 0.00 0.00 0.00 −3.89 −2.60UNK_AI643675 Al643675 109086_at 0.00 0.00 −1.83 0.00 −3.02 −2.24UNK_AI463271 AI463271 109488_at 0.00 0.00 0.00 0.00 −3.72 −3.74UNK_AW123076 AW123076 109774_at 0.00 −1.85 −1.71 0.00 −3.33 −2.06 PDK2AI848783 110330_at 0.00 −1.52 0.00 0.00 −4.15 −2.08 UNK_AI843917AI843917 111483_at 0.00 −1.37 0.00 0.00 −4.16 −3.11 UNK_AI451767AI451767 111525_at 0.00 0.00 0.00 0.00 −2.70 −2.28 UNK_AA289880 AA289880111547_at 0.00 0.00 0.00 0.00 −3.17 −2.26 UNK_AI851666 AI851666111970_at 0.00 −1.51 0.00 0.00 −4.74 −3.89 UNK_AI616223 AI616223112392_at 0.00 0.00 0.00 0.00 −4.82 −2.89 UNK_AI834768 AI834768112405_at 0.00 0.00 0.00 0.00 −5.07 −3.81 UNK_AI557974 AI557974112864_at 0.00 −1.75 −2.07 0.00 −2.50 0.00 UNK_AI849524 AI849524112986_at 0.00 0.00 0.00 0.00 −5.51 −5.79 UNK_AI849914 AI849914113545_at 0.00 −1.47 0.00 0.00 −2.87 −2.16 UNK_AI847141 AI847141113691_at 0.00 0.00 0.00 0.00 −3.69 −2.65 UNK_AW049533 AW049533114315_at 0.00 0.00 0.00 0.00 −2.70 −2.60 UNK_AW048818 AW048818114394_at 0.00 −2.13 0.00 0.00 −2.20 0.00 UNK_AW121080 AW121080114420_at 0.00 −3.91 −3.29 0.00 3.25 4.37 UNK_AA734866 AA734866114453_at 0.00 0.00 0.00 0.00 −4.76 −5.72 UNK_AI848077 AI848077114514_at 0.00 0.00 0.00 −2.37 −2.33 −1.99 UNK_AI605635 AI605635114553_at 0.00 0.00 0.00 0.00 −2.81 −2.15 UNK_AI414584 AI414584114556_at 0.00 −1.81 −1.54 0.00 −2.17 −2.03 UNK_AI451747 AI451747114685_at 0.00 −2.08 0.00 0.00 −2.83 0.00 UNK_AW123120 AW123120114743_at 0.00 0.00 0.00 0.00 −4.86 −4.13 UNK_AI591553 AI591553114775_at 0.00 0.00 0.00 0.00 −4.72 −2.22 UNK_AI005882 AI005882115070_at 0.00 0.00 −1.91 0.00 −4.34 −2.05 UNK_AA711252 AA711252115155_at 0.00 0.00 −1.72 0.00 −4.16 −3.45 UNK_AI853189 AI853189115199_at 0.00 0.00 0.00 0.00 −3.57 −2.34 UNK_AA667270 AA667270115201_at 0.00 0.00 0.00 0.00 −2.39 −2.04 UNK_AI851486 AI851486115236_at 0.00 −2.07 0.00 0.00 −3.28 −1.93 UNK_AA824120 AA824120115360_at 0.00 −1.81 0.00 0.00 −3.33 −2.68 UNK_AI839569 AI839569115467_at 0.00 0.00 0.00 0.00 −2.94 −2.13 UNK_AI852809 AI852809115539_at 0.00 −2.59 −1.92 0.00 −3.44 −1.93 UNK_AW045801 AW045801115575_at 0.00 0.00 0.00 0.00 −2.04 −2.26 UNK_AI853953 AI853953116042_at 0.00 0.00 −1.84 0.00 −3.19 −2.15 UNK_AI591726 AI591726116350_at 0.00 0.00 0.00 0.00 −5.09 −3.88 UNK_AA981270 AA981270116390_at 0.00 0.00 0.00 0.00 −3.43 −2.26 UNK_AI647836 AI647836116644_at 0.00 0.00 −1.97 0.00 −2.74 −2.31 UNK_AI882312 AI882312116747_at 0.00 −1.82 0.00 0.00 −3.27 −2.54 UNK_AI505458 AI505458116826_at 0.00 −1.98 −2.47 0.00 −4.71 −1.89 UNK_AA616199 AA616199117128_at 0.00 0.00 0.00 0.00 −2.27 −2.06 UNK_AI851602 AI851602117208_at 0.00 −1.93 −1.88 0.00 −3.27 −2.57 UNK_AI838208 AI838208117242_at 0.00 0.00 0.00 0.00 −5.22 −2.68 UNK_AI835553 AI835553117280_at 0.00 0.00 0.00 0.00 −4.97 −5.55 UNK_AI835075 AI835075128785_r_at 0.00 −2.02 0.00 0.00 −4.18 −1.97 UNK_AI049307 AI049307128829_at 0.00 −1.71 0.00 −1.71 −2.81 −2.11 UNK_AA624027 AA624027129503_at 0.00 −1.69 0.00 0.00 −3.59 −2.12 UNK_AI893884 AI893884129544_at 0.00 0.00 0.00 0.00 −3.45 −2.71 UNK_AI156198 AI156198130460_at 0.00 0.00 0.00 0.00 −2.29 −2.22 UNK_AI836434 AI836434130990_at 0.00 0.00 0.00 0.00 −2.19 −2.38 UNK_AW047063 AW047063131264_f_at 0.00 0.00 0.00 0.00 −2.03 −2.23 UNK_AA466676 AA466676132021_at 0.00 0.00 0.00 0.00 −2.04 −2.33 UNK_AI429239 AI429239132820_at 0.00 −2.10 0.00 −2.44 0.00 0.00 UNK_AI639670 AI639670133719_f_at 0.00 0.00 0.00 0.00 −2.62 −2.46 UNK_AI463563 AI463563133720_at 0.00 −1.88 0.00 0.00 −2.73 −3.37 UNK_AI464129 AI464129133838_at 0.00 −1.90 0.00 −2.11 −2.82 0.00 UNK_AA420328 AA420328134116_at 0.00 0.00 0.00 0.00 −2.70 −2.28 UNK_AI255188 AI255188135201_at 0.00 −3.44 −2.08 0.00 2.29 3.08 UNK_AA420078 AA420078136068_at 0.00 0.00 0.00 0.00 −2.93 −2.72 UNK_AI551047 AI551047136348_at 0.00 0.00 −1.98 0.00 −3.82 −3.36 UNK_AW146057 AW146057136535_at 0.00 0.00 −1.79 0.00 −2.03 −2.06 UNK_AI642422 AI642422137185_i_at 0.00 0.00 0.00 0.00 −2.57 −2.24 UNK_AI840674 AI840674138502_at 0.00 0.00 0.00 0.00 −2.66 −3.02 UNK_AI847438 AI847438139022_at 0.00 0.00 −1.88 0.00 −3.62 −2.20 UNK_AI427762 AI427762140015_at 0.00 0.00 0.00 0.00 −2.30 −2.18 UNK_AW215832 AW215832 92786_at0.00 0.00 0.00 0.00 −2.31 0.00 UNK_AI626942 AI626942 92845_at 0.00 0.000.00 0.00 −2.11 0.00 UNK_AI843232 AI843232 93138_at 0.00 0.00 0.00 0.00−2.26 0.00 UNK_AI853219 AI853219 93464_at 0.00 0.00 0.00 0.00 −2.24 0.00UNK_AI561567 AI561567 93478_at 0.00 0.00 0.00 −1.69 −1.83 −2.11UNK_AA612483 AA612483 93481_at 0.00 0.00 0.00 0.00 0.00 −2.06UNK_AI846720 AI846720 93560_at 0.00 −1.90 0.00 0.00 −2.31 −1.66UNK_AI845882 AI845882 93584_at 0.00 0.00 0.00 0.00 −2.69 −1.71 IGH-6V00821 93815_at 0.00 0.00 0.00 0.00 −2.17 0.00 UNK_AI839425 AI83942594010_g_at 0.00 0.00 0.00 0.00 −2.07 0.00 UNK_AI848888 AI84888894057_g_at −1.44 −2.04 0.00 0.00 −2.00 0.00 stearoyl-Coenzyme M21285 Adesaturase 1; Scd1 94080_at 0.00 0.00 0.00 0.00 −2.49 0.00 UNK_AI835718AI835718 94481_at 0.00 0.00 0.00 0.00 −2.14 −1.86 UNK_AI851321 AI85132194531_at 0.00 0.00 0.00 0.00 −3.06 −1.99 UNK_AW124582 AW124582 94554_at0.00 0.00 0.00 0.00 −2.75 0.00 UNK_AW120965 AW120965 94663_at 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0.00 −2.72 −1.42UNK_AA823920 AA823920 114316_at 0.00 0.00 0.00 0.00 −2.92 −1.69UNK_AI605358 AI605358 114392_at 0.00 0.00 0.00 0.00 −2.85 0.00UNK_AW120619 AW120619 114416_at 0.00 0.00 0.00 0.00 0.00 −3.51UNK_AW045985 AW045985 114418_at 0.00 0.00 0.00 0.00 −2.38 0.00UNK_AI854454 AI854454 114476_at 0.00 0.00 0.00 0.00 −2.89 0.00UNK_AI482420 AI482420 114478_at 0.00 0.00 0.00 0.00 0.00 −3.17UNK_AA061949 AA061949 114706_at 0.00 0.00 0.00 0.00 −2.32 −1.36UNK_AW049085 AW049085 114752_at 0.00 −2.01 0.00 0.00 0.00 2.84UNK_AI843572 AI843572 114794_at 0.00 −1.73 0.00 0.00 −2.33 −1.39UNK_AA693185 AA693185 114982_at 0.00 −1.59 0.00 0.00 −3.53 −1.98UNK_AA959852 AA959852 115077_f_at 0.00 0.00 0.00 0.00 −2.03 0.00 DBTAA896722 115078_r_at 0.00 0.00 0.00 0.00 −2.52 0.00 DBT AA896722115106_at 0.00 −1.49 0.00 0.00 −2.69 −1.92 UNK_AI851210 AI851210115169_at 0.00 0.00 0.00 0.00 −2.15 0.00 UNK_AW047351 AW047351 115323_at0.00 0.00 −1.34 0.00 −2.07 −1.72 UNK_AA107507 AA107507 115370_at 0.000.00 0.00 0.00 −2.38 0.00 UNK_AI527642 AI527642 115376_at 0.00 0.00 0.000.00 −2.23 0.00 UNK_AI850511 AI850511 115428_at 0.00 0.00 −1.95 0.00−3.82 0.00 UNK_AA673260 M673260 115437_at 0.00 −1.66 0.00 0.00 −2.21−1.37 UNK_AW049924 AW049924 115545_at 0.00 0.00 0.00 0.00 −2.29 0.00UNK_AA940371 M940371 115629_at 0.00 0.00 0.00 0.00 0.00 −3.06UNK_AA183896 AA183896 115640_at 0.00 0.00 0.00 0.00 −2.88 −0.66UNK_AI451541 AI451541 115686_at 0.00 0.00 0.00 0.00 −3.34 0.00UNK_AI853521 AI853521 115845_at 0.00 0.00 0.00 0.00 −2.24 −1.49UNK_AW107813 AW107813 115847_i_at 0.00 0.00 0.00 0.00 −2.07 −1.59UNK_AI327072 AI327072 116046_at 0.00 0.00 0.00 0.00 −2.42 0.00UNK_AI848153 AI848153 116151_at 0.00 0.00 −2.09 0.00 0.00 0.00UNK_AI845734 AI845734 116152_at 0.00 0.00 0.00 0.00 −5.30 −1.89UNK_AI840320 AI840320 116263_at 0.00 0.00 0.00 0.00 −2.20 −1.49UNK_AW060609 AW060609 116349_at 0.00 0.00 0.00 0.00 −2.01 0.00UNK_AI155885 AI155885 116406_at 0.00 0.00 0.00 0.00 0.00 −2.81UNK_AW050231 AW050231 116438_at 0.00 0.00 0.00 0.00 0.00 −2.92UNK_AI853912 AI853912 116466_at 0.00 0.00 0.00 0.00 −2.94 −1.80UNK_AI591541 AI591541 116661_at 0.00 0.00 0.00 0.00 −2.81 0.00UNK_AI594516 AI594516 116771_at 0.00 0.00 0.00 0.00 −2.16 −1.56UNK_AI843862 AI843862 116856_at 0.00 0.00 0.00 0.00 −2.08 0.00UNK_AW122439 AW122439 116887_at 0.00 0.00 0.00 0.00 −2.49 0.00UNK_AI848169 AI848169 116919_f_at 0.00 0.00 0.00 0.00 −3.43 −1.62UNK_AI837430 AI837430 116949_at 0.00 0.00 0.00 0.00 −2.30 −1.95UNK_AI835398 AI835398 116967_at 0.00 0.00 0.00 0.00 −2.74 −1.58UNK_AI851900 AI851900 116975_at 0.00 0.00 0.00 0.00 0.00 −2.24UNK_AI848908 AI848908 117008_at 0.00 0.00 0.00 0.00 −2.41 0.00UNK_AI836364 AI836364 117080_at 0.00 0.00 0.00 0.00 −4.41 −1.77UNK_AW046827 AW046827 117107_at 0.00 −1.73 −1.97 0.00 −3.77 −1.76UNK_AI837768 AI837768 117123_at 0.00 −2.18 0.00 0.00 −1.51 0.00UNK_AI840704 AI840704 117125_at 0.00 0.00 −0.03 0.00 −3.36 −0.88UNK_AI835705 AI835705 117178_at 0.00 0.00 0.00 0.00 −2.32 −1.81UNK_AI844448 AI844448 117206_at 0.00 0.00 0.00 0.00 −5.29 0.00UNK_AW122028 AW122028 117213_at 0.00 −1.74 0.00 0.00 −3.01 −1.60UNK_AI850929 AI850929 117307_at 0.00 0.00 0.00 0.00 −3.93 0.00UNK_AI844588 AI844588 117308_at 0.00 0.00 0.00 0.00 −2.09 0.00UNK_AI835357 AI835357 128879_f_at 0.00 0.00 0.00 0.00 −3.24 0.00UNK_AI838074 AI838074 129016_f_at 0.00 0.00 0.00 0.00 −1.50 −2.09UNK_AI596402 AI596402 129176_at 0.00 0.00 0.00 0.00 0.00 −13.63UNK_AI607324 AI607324 129231_at 0.00 −5.11 0.00 0.00 0.00 0.00UNK_AW046840 AW046840 129306_r_at 0.00 0.00 0.00 0.00 −2.42 −1.86UNK_AI606549 AI606549 129582_at 0.00 0.00 0.00 0.00 −2.32 −1.74UNK_AI465103 AI465103 130312_at 0.00 0.00 0.00 0.00 −1.96 −2.85UNK_AW215796 AW215796 130512_at 0.00 −1.69 0.00 0.00 −2.50 −1.87UNK_AI848603 AI848603 130696_f_at 0.00 0.00 0.00 −3.94 0.00 0.00UNK_AW210623 AW210623 130730_f_at 0.00 0.00 0.00 0.00 −1.91 −2.09UNK_AA270325 AA270325 132118_at 0.00 −1.73 0.00 −2.16 −1.93 −1.94UNK_AI642706 AI642706 133171_at 0.00 −2.00 −1.80 0.00 0.00 0.00UNK_AA683786 AA683786 133759_at 0.00 0.00 0.00 0.00 −2.61 0.00UNK_AI480951 AI480951 133886_at 0.00 0.00 0.00 0.00 −4.76 0.00UNK_AA168908 AA168908 134047_at 0.00 −1.88 0.00 0.00 −2.17 −1.74UNK_AW123320 AW123320 134281_at 0.00 0.00 0.00 0.00 −2.51 0.00UNK_AI551165 AI551165 134622_f_at −2.30 0.00 0.00 0.00 0.00 0.00UNK_AI641962 AI641962 134778_at 0.00 −1.98 −1.91 0.00 −2.80 −1.87UNK_AI666678 AI666678 135643_at 0.00 −2.73 0.00 0.00 0.00 0.00UNK_AA396310 AA396310 135691_at 0.00 −1.77 0.00 0.00 −2.36 −1.46UNK_AA882067 AA882067 136174_at 0.00 0.00 −1.68 0.00 −2.11 −1.50UNK_AW048956 AW048956 136545_at 0.00 −4.44 −1.77 0.00 −1.82 0.00UNK_AA982069 AA982069 136719_at 0.00 0.00 0.00 0.00 −2.50 0.00UNK_AI847908 AI847908 137973_at 0.00 −1.94 −1.65 0.00 −3.24 −1.85UNK_AI843877 AI843877 137979_at 0.00 −2.19 0.00 0.00 0.00 0.00UNK_AI848070 AI848070 138060_at 0.00 0.00 0.00 0.00 −2.00 0.00UNK_AW122571 AW122571 138086_f_at 0.00 0.00 0.00 0.00 −1.73 −2.25UNK_AW122816 AW122816 138556_at 0.00 0.00 0.00 0.00 0.00 −2.27UNK_AI874931 AI874931 139522_at 0.00 −1.48 0.00 0.00 −2.07 −1.56UNK_AW046420 AW046420 139980_g_at 0.00 0.00 0.00 0.00 −3.05 −1.67UNK_AI450646 AI450646 140519_at 0.00 0.00 0.00 0.00 −2.66 −1.97UNK_AI642378 AI642378 140861_at 0.00 −2.29 0.00 0.00 −1.43 0.00UNK_AI645591 AI645591 104962_at 0.00 0.00 0.00 0.00 0.78 −3.35 AA450473AA450473 93316_at 0.00 0.00 0.00 0.00 −2.00 0.00 UNK_AB017026 AB01702697172_s_at 0.00 0.00 0.00 0.00 −2.07 0.00 ABCC9 D86037 95425_at 0.000.00 0.00 0.00 −2.24 0.00 acetyl-Coenzyme A U21489 dehydrogenase, longchain; Acadl 92581_at 0.00 0.00 −1.93 0.00 −2.49 0.00 acetyl-Coenzyme AU07159 dehydrogenase, medium chain; Acadm 106070_at 0.00 0.00 −3.56 0.00−4.60 0.00 UNK_AI854239 AI854239 104650_at 0.00 0.00 0.00 0.00 0.00−8.36 acetylcholinesterase; X56518 Ache 101515_at 0.00 0.00 0.00 0.00−2.32 0.00 acyl-Coenzyme A AF006688 oxidase; Acox- pending 101028_i_at0.00 −1.72 −3.47 0.00 −3.72 −2.05 actin, alpha, cardiac; M15501 Actc193903_at 0.00 0.00 0.00 0.00 −3.07 0.00 activin receptor IIB; M84120Acvr2b 99671_at 0.00 −1.93 −2.01 0.00 0.00 1.51 adipsin; Adn X0467398999_at 0.00 0.00 0.00 0.00 −2.64 −1.88 ADSL AA606587 98435_at 0.000.00 0.00 0.00 −2.43 −2.03 adenylosuccinate M74495 synthetase 1, muscle;Adss1 111708_at 0.00 0.00 0.00 0.00 −2.33 −1.94 AF180471 AA70994497279_at 0.00 0.00 0.00 0.00 −2.14 0.00 UNK_AI837615 AI837615 110392_at0.00 0.00 0.00 0.00 −2.20 0.00 UNK_AA789854 AA789854 112429_at −1.97−1.95 −1.77 0.00 −2.77 0.00 UNK_AI462012 AI462012 112387_at 0.00 −2.450.00 0.00 −3.22 −2.31 UNK_AI747215 AI747215 99521_at 0.00 0.00 0.00 0.00−2.53 0.00 AK4 AB020239 92768_s_at 0.00 0.00 −2.85 −2.29 0.00 0.00aminolevulinic acid M15268 synthase 2, erythroid; Alas2 93500_at 0.000.00 0.00 0.00 −2.08 0.00 0 M63245 100068_at 0.00 −1.88 0.00 0.00 −3.32−1.91 alcohol M74570 dehydrogenase family 1, subfamily A2; Aldh1a2101489_at 0.00 0.00 0.00 0.00 −2.09 −2.05 AMD1 D12780 100323_at 0.000.00 −1.91 0.00 −2.12 0.00 AMD2 Z23077 100324_g_at 0.00 0.00 0.00 0.00−2.21 −1.84 AMD2 Z23077 101058_at 0.00 0.00 −2.85 0.00 −2.87 −2.06 AMY1J00356 100440_f_at 0.00 0.00 0.00 0.00 −3.30 −2.28 ANK1 U76758100441_s_at 0.00 0.00 0.00 0.00 −5.39 −2.20 ANK1 X69064 100439_i_at 0.000.00 0.00 0.00 −2.65 −1.95 ANK1 U76758 98476_at 0.00 0.00 −1.74 0.00−2.10 0.00 ANK3 L40631 98477_s_at 0.00 −1.84 0.00 0.00 −3.34 −1.89ankyrin 3, epithelial; L40632 AnK3 97786_at −1.75 0.00 0.00 0.00 −2.14−1.51 UNK_AJ011118 AJ011118 97235_f_at 0.00 −1.80 −2.29 0.00 −3.50 0.00APOBEC2 AW124988 93592_at −1.50 −3.36 0.00 0.00 0.00 0.00 apolipoproteinD; X82648 Apod 109808_at 0.00 0.00 0.00 0.00 −3.03 0.00 APOE AI504617102704_at −0.92 −4.95 −3.29 −4.01 −5.56 −3.77 aquaporin 4; Aqp4 U88623102703_s_at 0.00 −2.91 0.00 0.00 −3.94 −2.23 AQP4 U48398 102382_at 0.000.00 0.00 0.00 0.00 −2.46 ARNTL AB014494 99481_at 0.00 0.00 −1.98 0.00−2.90 −2.33 UNK_AI839697 AI839697 93664_at 0.00 0.00 0.00 0.00 0.00−2.07 ATP1B2 X16645 99570_s_at 0.00 −2.68 −1.76 −2.81 −1.98 0.00 ATP2A2AF029982 103699_i_at 0.00 −2.48 −3.08 0.00 −3.36 −2.40 UNK_AI646638AI646638 96035_at 0.00 0.00 −2.13 0.00 −2.59 −1.68 branched chain L47335ketoacid dehydrogenase E1, alpha polypeptide; Bckdha 102302_at 0.00 0.00−1.89 0.00 −2.21 0.00 BCKDHB L16992 103015_at 0.00 0.00 0.00 0.00 −2.040.00 B-cell U41465 leukemia/lymphoma 6; Bcl6 93836_at 0.00 −2.58 −2.530.00 −3.95 −1.74 BNIP3 AF041054 101903_at 0.00 0.00 0.00 0.00 −3.93−2.66 CD8beta opposite U76371 strand; Bop 94815_at 0.00 −1.91 −2.05 0.00−3.33 0.00 2,3- X13586 bisphosphoglycerate mutase; Bpgm 113861_at 0.000.00 0.00 0.00 −2.15 −1.61 BVES-PENDING AI152383 101128_at 0.00 0.000.00 0.00 −2.93 −2.12 calcium channel, L06234 voltage-dependent, L type,alpha 1S subunit; Cacna1s 99812_at 0.00 −1.79 0.00 0.00 −2.40 −2.09calpain 3; Capn3 X92523 99813_g_at 0.00 0.00 0.00 0.00 −2.54 −2.11calpain 3; Capn3 X92523 98079_at −2.36 −4.93 0.00 0.00 −13.32 −6.68CAR14 AB005450 92642_at 0.00 0.00 −2.16 0.00 −2.62 5.27 CAR2 M25944100600_at 0.00 0.00 0.00 0.00 −2.40 −2.04 CD24A M58661 93332_at 0.000.00 0.00 0.00 −2.65 −1.74 CD36 antigen; Cd36 L23108 101516_at 0.00 0.00−2.01 0.00 0.00 0.00 CD59 U60473 104743_at 0.00 0.00 0.00 0.00 −2.26−2.14 UNK_AB022100 AB022100 95471_at 0.00 −2.68 −2.76 0.00 2.10 1.92cyclin-dependent U22399 kinase inhibitor 1C (P57); Cdkn1c 104209_at 0.000.00 0.00 0.00 −6.63 −3.70 CHRP AI847016 99994_at 0.00 0.00 −2.89 0.51−3.44 0.00 CIDEA AF041376 94463_at 0.00 0.00 0.00 0.00 −5.15 0.00chloride channel 3; X78874 Clcn3 94464_at 0.00 −1.75 0.00 0.00 −2.12−1.59 CLCN3 AF029347 94465_g_at 0.00 0.00 0.00 0.00 −2.01 −1.32 CLCN3AF029347 92322_at 0.00 0.00 −2.94 −1.65 −2.57 0.00 cathelin-likeprotein; X94353 Cnlp 93582_at 0.00 0.00 0.00 0.00 −2.10 0.00 COQ7AF080580 102749_at 0.00 0.00 −1.45 0.00 −2.37 −1.32 COX7A1 AF037370113828_at 0.00 −2.35 −2.07 0.00 −4.31 −2.24 CPT1B AA189179 102951_at0.00 0.00 0.00 0.00 0.00 −2.03 CRADD AJ224738 103646_at 0.00 0.00 −1.750.00 −2.43 −1.81 carnitine X85983 acetyltransferase; Crat 99065_at 0.000.00 0.00 −2.08 0.00 0.00 casein kappa; Csnk M10114 97336_at 0.00 −2.650.00 0.00 0.00 2.12 UNK_AJ131851 AJ131851 98132_at 0.00 0.00 0.00 0.00−3.97 0.00 cytochrome c, X01756 somatic; Cycs 93996_at 0.00 −4.02 −5.63−4.92 −3.73 0.00 CYP2E1 X01026 94526_at 0.00 0.00 0.00 0.00 −2.34 0.00UNK_AI848453 AI848453 96757_at 0.00 0.00 −2.06 0.00 −3.05 −1.95D10JHU81E AI852165 109645_at 0.00 0.00 0.00 0.00 −2.03 −1.59UNK_AW123377 AW123377 113324_at 0.00 0.00 0.00 0.00 −2.47 0.00UNK_AI121830 AI121830 96803_at 0.00 0.00 0.00 0.00 −2.32 0.00UNK_AW210370 AW210370 96346_at 0.00 −1.46 −2.12 0.00 2.45 5.93 D18UCLA3AI854020 133703_at 0.00 0.00 0.00 0.00 −2.52 −2.07 UNK_AI462192 AI46219295594_at 0.00 −2.01 −2.26 0.00 −2.86 −2.01 UNK_AI847486 AI84748693614_at 0.00 0.00 0.00 0.00 −4.05 −4.34 UNK_AA600647 AA600647 99959_at0.00 0.00 0.00 0.00 −2.42 0.00 UNK_AW061337 AW061337 97397_at 0.00 0.000.00 0.00 −2.35 −1.50 UNK_AI848344 AI848344 113212_at 0.00 0.00 0.000.00 −4.09 −1.85 UNK_AI848538 AI848538 102859_at 0.00 −1.90 0.00 0.00−2.02 −1.80 UNK_AW121304 AW121304 96112_at 0.00 0.00 0.00 0.00 −2.150.00 UNK_AI851178 AI851178 112421_at 0.00 −2.29 0.00 0.00 −6.07 −3.49UNK_AI838528 AI838528 103617_at 0.00 0.00 0.00 0.00 −2.42 0.00 decayaccelerating D63679 factor 1; Daf1 98966_at 0.00 0.00 0.00 0.00 −2.58−0.74 dihydrolipoamide L42996 branched chain transacylase E2; Dbt98527_at 0.00 −2.22 0.00 0.00 −3.37 −2.02 dodecenoyl- Z14050 Coenzyme Adelta isomerase (3,2 trans- enoyl-Coenyme A isomerase); Dci 95478_at0.00 0.00 0.00 0.00 −2.07 −1.81 DEB1 AW124231 99485_at 0.00 0.00 0.000.00 −2.08 0.00 DFFA AB009376 108255_at 0.00 0.00 0.00 0.00 −2.29 −2.60DUSP13 AA144705 100311_f_at 0.00 0.00 −2.37 0.00 0.00 0.00 EAR1 U72032103240_f_at 0.00 0.00 −3.40 0.00 0.00 0.00 EAR3 AF017258 93754_at 0.000.00 0.00 0.00 −2.05 0.00 enoyl coenzyme A AF030343 hydratase 1,peroxisomal; Ech1 102774_at 0.00 −1.77 0.00 0.00 −2.89 −1.98 epidermalgrowth V00741 factor; Egf 94353_at 0.00 0.00 0.00 0.00 0.00 −2.24eukaryotic U75530 translation initiation factor 4E binding protein 2;Eif4ebp2 93051_at 0.00 −2.61 0.00 0.00 −2.14 0.00 EPHX2 Z37107101538_i_at 0.00 −4.79 −3.78 0.00 −7.47 −1.63 ES1 AW226939 101539_f_at0.00 −3.93 −3.37 0.00 −7.31 0.00 ES1 AW226939 103964_at 0.00 −1.62 −1.630.00 −2.22 0.00 estrogen related U85259 receptor, alpha; Esrra 115969_at0.00 0.00 0.00 0.00 −2.50 0.00 EXTL1 AI850861 94214_at 0.00 −2.71 0.000.00 −3.30 0.00 FABP3 X14961 94507_at 0.00 0.00 0.00 0.00 −2.62 0.00fatty acid Coenzyme U15977 A ligase, long chain 2; Facl2 98575_at 0.00−1.34 −3.15 −2.39 −3.33 0.00 fatty acid synthase; X13135 Fasn 100928_at−4.16 0.00 0.00 2.21 −0.01 19.58 fibulin 2; Fbln2 X75285 97379_at −0.89−3.22 −4.99 0.00 −7.21 −4.72 fructose D42083 bisphosphatase 2; Fbp297518_at 0.00 −3.76 −2.66 0.00 −2.48 −1.86 famesyl diphosphate D29016famesyl transferase 1; Fdft1 92587_at 0.00 0.00 0.00 0.00 −2.01 0.00ferredoxin 1; Fdx1 L29123 97213_at 0.00 −2.01 −2.18 0.00 −3.49 −2.34FEM1A AF064447 100494_at 0.00 0.00 0.00 0.00 −3.74 0.00 FGF1 M30641103995_at 0.00 0.00 0.00 0.00 −2.00 −2.32 FGFBP1 AF065441 102366_at 0.000.00 −5.06 −3.75 0.00 2.31 UNK_AA718169 AA718169 101991_at 0.00 −2.610.00 0.00 −1.59 1.77 flavin containing D16215 monooxygenase 1; Fmo1104607_at 0.00 0.00 −1.82 0.00 −2.08 −1.72 UNK_AF093624 AF09362499121_at 0.00 0.00 0.00 0.00 −2.20 0.00 fragile X mental X90875retardation gene, autosomal homolog; Fxr1h 97430_at 0.00 −2.17 0.00 0.00−3.62 −2.00 G6PT1 AF080469 104616_g_at 0.00 0.00 0.00 0.00 −3.11 0.00galactose-1- M96265 phosphate uridyl transferase; Galt 102967_at 0.000.00 0.00 −1.64 −2.62 −2.68 GDAP1 Y17850 92592_at 0.00 0.00 0.00 0.00−3.62 −2.07 GDC1 M25558 97155_at −1.62 0.00 0.00 0.00 −4.30 −2.94myostatin; Mstn U84005 98984_f_at 0.00 0.00 0.00 0.00 −5.39 −2.75glycerol phosphate D50430 dehydrogenase 1, mitochondrial; Gdm1 99107_at0.00 −2.02 0.00 0.00 −1.80 0.00 GHR M31680 102060_at 0.00 −2.08 0.000.00 −1.92 −1.63 GOLGA4 AF051357 100573_f_at 0.00 −1.98 −1.95 0.00 −2.35−1.80 GPI1 M14220 113915_at 0.00 −2.92 −3.65 −4.26 −4.95 −3.03UNK_AI226254 AI226254 93750_at 0.00 −2.13 −2.15 0.00 −1.75 0.00gelsolin; Gsn J04953 112869_at 0.00 0.00 0.00 0.00 −2.44 −2.45GSNPAT-PENDING AI852572 96085_at 0.00 0.00 0.00 0.00 0.00 −2.36 GSTA4L06047 93543_f_at 0.00 0.00 −1.85 0.00 −2.20 0.00 GSTM1 J03952102094_f_at 0.00 0.00 0.00 0.00 −3.22 −1.46 GSTM1 AI841270 95445_at 0.000.00 0.00 0.00 −1.96 −2.10 GUKMI1 AW124194 100597_at 0.00 0.00 0.00 0.00−2.22 0.00 GYG1 AW049730 98496_at 0.00 −2.01 0.00 0.00 −2.49 −1.83 GYS3U53218 95485_at 0.00 0.00 −1.89 0.00 −2.61 0.00 hydroxylacyl- D29639Coenzyme A dehydrogenase- dehydrogenase; Hadh 94781_at −1.29 −1.94 −2.84−2.71 −1.65 0.00 hemoglobin alpha, V00714 adult chain 1; Hba- a1103534_at −1.77 −1.81 −3.81 0.00 −2.23 1.56 hemoglobin, beta V00722adult minor chain; Hbb-b2 94375_at 0.00 0.00 0.00 0.00 −2.10 −1.94hexokinase 2; Hk2 Y11666 92568_at 0.00 0.00 0.00 0.00 −1.92 −2.02house-keeping M74555 protein 1; Hkp1 102714_at 0.00 0.00 0.00 0.00 −1.87−2.08 HSC70T L27086 97867_at 0.00 −2.03 0.00 0.00 0.00 0.00hydroxysteroid 11- X83202 beta dehydrogenase 1; Hsd11b1 102620_at 0.000.00 0.00 0.00 −7.64 −4.63 UNK_AF088983 AF088983 97914_at 0.00 0.00 0.000.00 −2.02 −1.92 heat shock protein, D17666 74 kDa, A; Hspa9a 95693_at0.00 −2.56 −2.35 0.00 −2.04 −1.82 isocitrate U51167 dehydrogenase 2(NADP+), mitochondrial; Idh2 93029_at 0.00 0.00 0.00 0.00 −2.22 0.00isocitrate U68564 dehydrogenase 3 (NAD+), gamma; Idh3g 103904_at 0.00−2.69 −2.38 0.00 0.00 0.00 insulin-like growth X81584 factor bindingprotein 6; Igfbp6 96764_at −2.18 0.00 4.23 4.92 2.47 10.03 UNK_AJ007971AJ007971 110795_at 0.00 0.00 0.00 0.00 −2.27 0.00 JDP1-PENDING AI85244594193_at 0.00 0.00 −3.26 0.00 −3.75 −2.14 KCNA7 AF032099 98787_at 0.000.00 0.00 0.00 0.00 −4.22 potassium inwardly D50581 rectifying channel,subfamily J, member 11; Kcnj11 102849_at 0.00 0.00 −3.01 0.00 0.00 0.00potassium inwardly- D88159 rectifying channel, subfamily J, member 8;Kcnj8 94379_at 0.00 −2.47 −1.93 0.00 −2.35 −2.21 kinesin heavy chainD17577 member 1B; Kif1b 93527_at 0.00 −2.06 −2.23 0.00 0.00 0.00 KLF9Y14296 93528_s_at 0.00 −1.98 0.00 0.00 −2.51 0.00 KLF9 AI848050 94321_at0.00 0.00 0.00 0.00 −2.29 0.00 keratin complex 1, V00830 acidic, gene10; Krt1- 10 97976_at 0.00 0.00 0.00 0.00 −2.24 0.00 kinectin 1; Ktn1L43326 92366_at 0.00 −2.03 0.00 0.00 0.00 0.00 laminin, alpha 2; U12147Lama2 101990_at 0.00 −3.06 −2.70 0.00 −3.72 −1.80 lactate X51905dehydrogenase 2, B chain; Ldh2 96608_at 0.00 0.00 0.00 0.00 −2.42 0.00lupus nephritis- AF023463 associated peptide 1; Lnap1 113140_at 0.000.00 0.00 0.00 −3.11 −2.24 LOC56046 AI846417 103090_at 0.00 0.00 0.000.00 0.00 −2.06 LOC56046 AI838742 99536_at 0.00 0.00 0.00 0.00 −2.79−2.17 UNK_AB016080 AB016080 112850_at 0.00 −1.89 −1.68 0.00 −2.20 −2.12UNK_AW121352 AW121352 101115_at 0.00 0.00 0.00 −2.20 −2.15 −0.12lactotransferrin; Ltf J03298 130772_at 0.00 −2.36 −2.24 0.00 0.00 0.00LYNX1 AI838844 137205_f_at 0.00 0.00 0.00 0.00 −2.71 0.00 LYNX1 AI839851102828_at 0.00 0.00 0.00 0.00 −2.31 −1.54 mitogen activated U39066protein kinase kinase 6; Map2k6 102829_s_at 0.00 0.00 0.00 0.00 −2.060.00 MAP2K6 X97052 102431_at 0.00 0.00 0.00 0.00 −0.45 −2.09 MTAPTM18775 102742_g_at 0.00 0.00 0.00 0.00 −1.89 −2.98 MTAPT M18775 96311_at0.00 −2.37 0.00 0.00 −3.29 −2.09 MBP M11533 97282_at −11.15 0.00 0.000.00 0.00 0.00 MELA D10049 103838_at 0.00 0.00 0.00 0.00 −2.36 −1.98MG29 AB010144 102061_at 0.00 −3.00 −3.32 −3.75 −5.64 −2.29 MLF1 AF100171103622_at −1.34 0.00 0.00 0.00 −2.19 −1.80 UNK_AW050255 AW05025596348_at 0.00 −2.13 0.00 0.00 −2.20 0.00 UNK_AW121217 AW121217 101082_at0.00 0.00 −2.34 0.00 −2.56 −1.12 MOD1 J02652 102096_f_at 0.00 0.00 −2.420.00 0.00 3.13 MUP1 AI255271 101909_f_at 0.00 0.00 −4.14 0.00 0.00 3.70MUP3 M16357 100017_at −1.56 0.00 0.00 0.00 −2.75 0.00 myosin-bindingU68267 protein H; Mybph 97990_at 0.00 0.00 0.00 0.00 −2.28 0.00 myosinheavy chain D85923 11, smooth muscle; Myh11 98616_f_at 0.00 −8.12 −2.13−32.76 −4.63 −4.81 MYHCB AJ223362 93050_at 0.00 −2.77 0.00 0.00 −2.91−2.11 myosin light chain, M91602 phosphorylatable, cardiac ventricles;Mylpc 94122_at 7.47 3.44 2.58 0.00 −3.81 −1.94 MYOC AF041335 92407_at0.00 −1.90 0.00 0.00 −3.23 −2.03 MYOM1 AJ012072 102041_at 0.00 0.00 0.000.00 −2.53 −1.90 MYOM2 AJ001038 92876_at 0.00 0.00 0.00 0.00 −4.44 −2.04NADH AA590675 dehydrogenase (ubiquinone) Fe—S protein 4 (18 kDa); Ndufs493006_at 0.00 0.00 0.00 0.00 −4.91 −2.79 NFIC Y07693 96153_at 0.00 0.00−4.66 −8.35 −10.04 −5.56 neutrophilic granule L37297 protein; Ngp92824_at 0.00 0.00 0.00 0.00 −2.29 −1.91 NM23-M6 AF051942 99009_at 0.00−2.54 0.00 0.00 −2.06 0.00 nicotinamide Z49204 nucleotidetranshydrogenase; Nnt 98365_at 0.00 0.00 0.00 0.00 0.00 −2.02 nitricoxide synthase D14552 1, neuronal; Nos1 102371_at 0.00 0.00 0.00 0.00−3.52 −2.20 nuclear receptor X16995 subfamily 4, group A, member 1;Nr4a1 92362_at 0.00 0.00 0.00 0.00 0.00 −2.83 NTTP1 X95518 99549_at 0.00−3.17 0.00 0.00 3.34 2.12 osteoglycin; Ogn D31951 104479_at 0.00 0.000.00 0.00 −4.22 −5.06 purinergic receptor L14751 P2Y, G-protein coupled2; P2ry2 113762_at 0.00 0.00 0.00 0.00 −2.71 0.00 UNK_AI510151 AI51015196735_at 0.00 0.00 0.00 0.00 0.00 −2.76 UNK_AW049732 AW049732 93308_s_at0.00 0.00 0.00 −1.80 −4.41 0.00 PCX M97957 100489_at 0.00 0.00 0.00 0.000.00 −2.12 phosphodiesterase U68171 7A; Pde7a 115211_at 0.00 0.00 0.000.00 −2.66 −1.52 PDHX AA987055 103526_at 0.00 0.00 0.00 0.00 −3.17 −2.61peptidyl arginine D16580 deiminase, type II; Pdi2 102049_at −1.92 0.000.00 0.00 −2.30 0.00 PDK4 AJ001418 103297_at 0.00 0.00 −5.49 0.00 −5.13−4.79 6-phosphofructo-2- X98848 kinase/fructose-2,6- biphosphatase 1;Pfkfb1 93567_at 0.00 0.00 0.00 0.00 −2.14 −1.90 PFN2 AW122536 92599_at0.00 0.00 0.00 0.00 −2.14 −1.47 PGAM2 AF029843 94733_at 0.00 −1.95 −2.18−1.90 −2.98 −1.72 P glycoprotein 2; J03398 Pgy2 94855_at 0.00 0.00 0.000.00 −4.56 −3.15 prohibitin; Phb X78682 92519_at 0.00 −2.02 −2.13 0.00−2.66 −2.06 phosphorylase X74616 kinase alpha 1; Phka1 97094_at 0.000.00 −2.50 0.00 −5.08 −2.05 phosphorylase J03293 kinase gamma; Phkg107109_at 0.00 0.00 0.00 0.00 −4.21 −2.18 PHRET1 AI835608 104431_at 0.000.00 0.00 0.00 −3.03 −1.83 protein kinase C, D11091 theta; Pkcq 98004_at0.00 0.00 0.00 0.00 −2.53 −2.11 protein kinase M63554 inhibitor, alpha;Pkia 98005_at 0.00 0.00 0.00 0.00 −2.57 −1.86 PKIA AW125442 113154_at0.43 0.00 −2.71 −1.11 −2.08 2.44 UNK_AI854500 AI854500 96114_at 0.000.00 0.00 0.00 −2.25 0.00 UNK_AW122076 AW122076 93933_at 0.00 0.00 0.000.00 −2.41 −2.58 protein phosphatase U89924 1, regulatory (inhibitor)subunit 5; Ppp1r5 97989_at 0.00 0.00 0.00 0.00 −2.59 −1.60 proteinphosphatase M81483 3, catalytic subunit, beta isoform; Ppp3cb 96256_at0.00 0.00 0.00 0.00 −2.17 0.00 peroxiredoxin 3; M28723 Prdx3 97096_at0.00 0.00 0.00 0.00 −5.20 −2.84 protein kinase, J02935 cAMP dependentregulatory, type II alpha; Prkar2a 100595_at 0.00 0.00 0.00 0.00 −2.330.00 PTP4A2 AF035644 101027_s_at 0.00 −1.93 0.00 0.00 −2.20 −1.52 PTTG1AF069051 96720_f_at 0.00 0.00 0.00 0.00 −2.67 0.00 parvalbumin; PvaX59382 104098_at 0.00 −2.59 −2.95 −3.60 −3.43 −2.09 peroxisomal L28835membrane protein 2, 22 kDa; Pxmp2 92410_at 0.00 0.00 0.00 0.00 0.00−2.59 RAD23a homolog X92410 (S. cerevisiae); Rad23a 104680_at 0.00 −2.27−2.19 0.00 0.00 0.00 RAMP1 AJ250489 100562_at 0.00 0.00 0.00 0.00 −3.97−3.48 UNK_AI846319 AI846319 99951_at 0.00 0.00 0.00 0.00 0.00 −4.08 RORCAF019660 98464_at 0.00 0.00 0.00 0.00 −2.35 0.00 UNK_AW124196 AW12419696296_at 0.00 0.00 0.00 0.00 −2.25 0.00 RPML7 AI843685 98007_at 0.00−3.41 −2.82 −3.72 −3.18 −2.45 RPS6KA2 AJ131021 92237_at 0.00 0.00 0.000.00 −9.91 −5.35 retinoid X receptor X66225 gamma; Rxrg 103448_at 0.002.51 −4.75 −1.37 −6.47 3.81 S100 calcium M83218 binding protein A8(calgranulin A); S100a8 103887_at 4.41 0.00 −8.99 −5.52 −6.50 5.43 S100calcium- M83219 binding protein A9 (calgranulin B); S100a9 102763_at0.00 0.00 0.00 0.00 −2.52 −1.62 UNK_AF064748 AF064748 102712_at −3.842.96 4.98 8.61 4.23 0.00 serum amyloid A 3; X03505 Saa3 99665_at 0.000.00 −2.09 −2.05 −3.58 −2.00 special AT-rich U05252 sequence bindingprotein 1; Satb1 111448_f_at 0.00 −1.94 −1.73 0.00 −2.64 −1.81 SATB1AI121993 111449_r_at 0.00 0.00 0.00 0.00 −2.19 0.00 SATB1 AI121993103399_at 0.00 0.00 0.00 0.00 0.00 −2.01 SCML1 AI853225 102808_at 0.000.00 0.00 0.00 −2.21 −1.64 sodium channel, L48687 voltage-gated, type I,beta polypeptide; Scn1b 94140_at 0.48 2.44 −2.79 0.00 0.00 0.00 SCVRM59446 92742_at 0.00 −4.88 0.00 0.00 −2.58 −1.69 SCYA11 U77462 98624_at0.00 −1.98 −2.23 0.00 −2.88 −2.07 seb4 protein; Seb4 X75316 103395_at0.00 0.00 0.00 0.00 −2.03 −1.79 SGCA AF019564 101394_at 0.00 0.00 0.000.00 −2.25 0.00 SGCG AB024922 96204_at 0.00 0.00 0.00 0.00 −2.53 0.00SH3BGR AJ239082 102208_at 0.00 −1.79 −2.13 0.00 −2.43 0.00 ST3GALVIAI153959 99320_at 0.00 0.00 0.00 0.00 −2.62 0.00 sialyltransferase 8X98014 (alpha 2, 8 sialytransferase) E; Siat8e 92722_f_at 0.00 0.00 0.000.00 −2.03 0.00 sine oculis-related X80339 homeobox 1 homolog(Drosophila); Six1 93000_g_at −2.80 −2.40 0.00 0.00 0.00 0.00 SIX4D50416 93001_at −1.65 0.00 0.00 0.00 −2.44 0.00 sine oculis-relatedD50418 homeobox 4 homolog (Drosophila); Six4 102314_at 0.00 −2.97 0.000.00 −4.23 −2.74 solute carrier family M23383 2 (facilitated glucosetransporter), member 4; Slc2a4 109069_at 0.00 −2.82 −2.00 0.00 0.00 3.28SLC39A1 AI255982 96926_at −2.06 −2.87 −2.56 0.00 0.00 0.00 UNK_AA980164AA980164 96042_at 0.00 0.00 0.00 0.00 −2.94 0.00 SOD2 L35528 92302_at0.00 0.00 −1.87 0.00 −2.80 0.00 Son of sevenless Z11664 homolog 2.(Drosophila); Sos2 92726_at 0.00 0.00 0.00 0.00 −3.87 −2.50 SOX6AJ010605 113125_at 0.00 0.00 0.00 0.00 −3.81 −2.03 UNK_AI851671 AI851671100952_at 0.00 0.00 0.00 0.00 −2.38 −2.24 stromal Interaction U47323molecule 1; Stim1 92888_s_at 0.00 0.00 0.00 0.00 −2.62 −1.73 proteintyrosine U34973 phosphatase-like unspliced c-terminal product andspliced c-terminal end STYX; hStyxb 93501_f_at 0.00 0.00 0.00 0.00 −2.610.00 SUCLA2 AF058955 93502_r_at 0.00 0.00 0.00 0.00 −4.71 0.00 SUCLA2AF058955 96268_at 0.00 0.00 0.00 0.00 −2.29 0.00 UNK_AI840979 AI840979100587_f_at 0.00 0.00 0.00 0.00 −2.02 0.00 SUPT4H AI843959 93994_at 0.000.00 0.00 0.00 −2.00 0.00 SYCP3 AW212131 102221_at 0.00 0.00 0.00 0.00−2.28 −1.75 SYNGR1 AJ002306 100355_g_at 0.00 0.00 0.00 0.00 −2.24 −1.51TBX14 AF013282 102256_at 0.00 0.00 0.00 0.00 −2.14 0.00 TBX15 AF041822102344_s_at 0.00 −2.14 −2.56 −4.39 −4.38 −2.48 TCEA3 AI132239 97402_at−2.80 −5.83 −4.24 −3.96 −4.97 −2.21 thioether S- M88694methyltransferase; Temt 101964_at 0.00 0.00 −2.16 0.00 0.00 3.47transketolase; Tkt U05809 92224_at 0.00 −5.01 0.00 0.00 0.00 0.00tetranectin X79199 (plasminogen- binding protein); Tna 101063_at 0.00−3.19 0.00 0.00 0.00 −2.68 troponin C, M29793 cardiac/slow skeletal;Tncc 98561_at 0.00 −3.08 0.00 0.00 0.00 −2.24 UNK_AJ242874 AJ24287493532_at 0.00 0.00 0.00 0.00 −2.52 0.00 troponin I, skeletal, J04992fast 2; Tnni2 101383_at 0.00 −2.85 0.00 0.00 −1.69 −1.97 TNNT1 AJ13171199532_at 0.00 0.00 0.00 0.00 −2.17 0.00 transducer of ErbB- D78382 2.1;Tob1 101446_at 0.00 0.00 0.00 0.00 −2.49 0.00 TPD52L1 AF004428 93266_at0.00 −2.33 −1.90 0.00 −2.55 −2.51 tropomyosin 5; U04541 Tpm5 93509_at0.00 0.00 −1.82 0.00 −2.58 −2.00 UBE2B U57690 99507_at 0.00 0.00 −3.440.00 −2.86 −1.60 UCP M21247 93392_at −1.48 −1.66 0.00 0.00 −2.72 −1.67UCP3 AB010742 95537_at 0.00 0.00 0.00 0.00 −2.26 0.00 ULK2 AB01957792820_at 0.00 0.00 0.00 0.00 −2.43 −2.13 USP2 AI846522 92821_at 0.000.00 0.00 0.00 −2.73 −1.71 USP2 AF079565 114088_at 0.00 0.00 0.00 0.00−2.55 −1.55 VAMP1 AI850070 92496_at 0.00 0.00 0.00 0.00 0.00 −2.59 VAMP5AF035643 103001_at 0.00 −2.17 −1.96 0.00 −3.42 −2.12 vascularendothelial U43836 growth factor B; Vegfb 98549_at 0.00 −1.87 0.00 0.00−2.11 0.00 vitronectin; Vtn M77123 115141_at 0.00 0.00 −3.89 0.00 −5.600.00 UNK_AW049840 AW049840 103824_at −1.39 −2.00 −2.01 0.00 −1.92 −1.71WFS1 AF084482 103238_at 0.00 0.00 0.00 0.00 −4.41 0.00 wingless-relatedM89797 MMTV integration site 4; Wnt4 96063_at 0.00 0.00 0.00 0.00 −2.020.00 X-ray repair X66323 complementing defective repair In Chinesehamster cells 5; XrccS 99932_at 0.00 0.00 0.00 0.00 0.00 −6.45 ZFP100U14556 101456_at 0.00 0.00 0.00 0.00 −2.16 −1.95 ZFP106 AF060245108046_at 0.00 0.00 0.00 0.00 −2.37 −2.19 ZFP238 AI844802

[0360] TABLE 5 BMP-2-induced changes in the expression of known genespreviously associated with bone or cartilage metabolism. Gene TitleSymbol GenBank Day 1 Day 2 Day 3 Day 4 Day 7 Day 14 Cell SurfaceProteins OSTEO- Osf2 D13664 2.1 +/− 0.2 4.1 +/− 0.6 7.4 +/− 0.2 11.6 +/−0.3   64.3 +/− 6.7  42.7 +/− 12   BLAST SPECIFIC FACT. 2 MEGAKAR. Prg4AB034730 0 +/− 0 5.6 +/− 0.2 4.3 +/− 0.2 4.8 +/− 0.1   0 +/− 0 0 +/− 0STIM. FACT. CADHERIN Cdh11 D21253 0 +/− 0 2.1 +/− 0.3 2.9 +/− 0   5.5+/− 3.3   37.9 +/− 9.6  38.2 +/− 7.3  11 CD44 Cd44 M27129 0 +/− 0 3.2+/− 0.5 3.9 +/− 0.1 4.3 +/− 0.3   4.5 +/− 0.2   6 +/− 0.6 ANTIGENCADHERIN Cdh2 AB008811 0 +/− 0 0 +/− 0 0 +/− 0 2.1 +/− 0.5   15.9 +/−1.5  14.6 +/− 0.2  2 SYNDECAN Sdc2 U00674 0 +/− 0 0 +/− 0 0 +/− 0 0 +/−0   4.1 +/− 1.2 4.5 +/− 0.2 2 INTEGRIN Itgav U14135 0 +/− 0 0 +/− 0 0+/− 0 0 +/− 0   4.4 +/− 1.4 5.7 +/− 1   ALPHA V (CD51) NEURAL NcamX07233 0 +/− 0 0 +/− 0 0 +/− 0 4 +/− 1.3 7.8 +/− 1.9 3.4 +/− 0.6 CELLADHESION MOLECULE SYNDECAN Sdc1 X15487 0 +/− 0 2 +/− 0.6 0 +/− 0 0 +/−0   7.2 +/− 1   6.9 +/− 0.2 1 L-34 Lgals3 X16074 0 +/− 0 1.6 +/− 0.3 2.1+/− 0.5 2.4 +/− 0.5     6 +/− 0.9 8.4 +/− 0.9 GALACTO- SIDE- BINDINGLECTIN. GAP JUNC. Gja1 X61576 0 +/− 0 2.3 +/− 0.5 0 +/− 0 4 +/− 0.8 8.4+/− 1.9 14.8 +/− 3.6  MEMB. CHANN. PROT. ALPHA 1 INTEGRIN Itgb3 AF0265090 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   0 +/− 0 7.2 +/− 1   BETA 3 (CD61)INTEGRIN Itgb2 X14951 2.6 +/− 0.6   3 +/− 0.3 2.8 +/− 1.1 2.9 +/− 0.3  2.9 +/− 1.1 8.8 +/− 0.1 BETA 2 (CD18) VASCULAR Vcam1 X67783 0 +/− 0 2.2+/− 0   0 +/− 0 2.9 +/− 0.6   3.5 +/− 0.9 6.8 +/− 1.4 CELL ADHESIONMOLECULE 1 Cytokines CONNEC- Ctgf M70642 5.1 +/− 0.8 8 +/− 1 10.2 +/−3.1  5.8 +/− 1.7   19.1 +/− 3.1  9.6 +/− 0.5 TIVE TISSUE GROWTH FACTORSTROMAL Sdf5 D50462 2.2 +/− 0.8 4.6 +/− 0.5 8.3 +/− 2.3 10.2 +/− 3.4  17.5 +/− 1.6  10.1 +/− 1.1  CELL DERIVED FACT. 5 MONO. Scya8 AB023418 0+/− 0 3.9 +/− 1.8   6 +/− 2.3 9 +/− 2.3 9.4 +/− 1.3 4.8 +/− 2   CHEMO-ATTRAC. PROT.-2 PRECUR. SMALL Scya2 J04467 3.3 +/− 0.6 7.4 +/− 1.4 8.5+/− 1.9 8.4 +/− 0.6   5.9 +/− 0.9 1.9 +/− 1   INDUCIB. CYTOKINE A2 IL-1BETA II1b M15131 1.1 +/− 1.9 5.4 +/− 2   4.4 +/− 2.1 4.3 +/− 1.1   0 +/−0 5.4 +/− 0.9 CYSTEINE Cyr61 M32490 1.7 +/− 0.5 2.6 +/− 0.3 5.2 +/− 0.37.8 +/− 2.3   6.4 +/− 1.8 2.8 +/− 0.7 RICH PROT. 61 TGF, BETA Tgfb1M13177 0 +/− 0 2.6 +/− 0.5 0 +/− 0 2.9 +/− 0.7   11.3 +/− 0.8  7.6 +/−0.7 1 MIDKINE Mdk M35833 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   22.2 +/− 1.8 10.9 +/− 1.5  INHIBIN Inhba X69619 0 +/− 0 1.5 +/− 0.4   2 +/− 0.7 4.9+/− 4.4   5.2 +/− 2.8 0 +/− 0 BETA-A WNT1 Wisp2 AF126063 0 +/− 0 0 +/− 00 +/− 0 0 +/− 0   0 +/− 0 4.3 +/− 0.3 INDUCIB. SIG. PATHWAY PROT. 2STROMAL Sdf1 D43805 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   0 +/− 0 6.7 +/−1   CELL DERIVED FACT. 1 COLONY Csf1 M21149 2.8 +/− 0.6 3 +/− 1 1.9 +/−0.1 0 +/− 0   3.1 +/− 0.7 5.3 +/− 0.7 STIM. FACT. 1 (MACRO- PHAGE) PDGF,Pdgfa M29464 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   5.7 +/− 1.4 0 +/− 0 ALPHATGF, BETA Tgfb3 M32745 0 +/− 0 0 +/− 0 0 +/− 0 2.6 +/− 0.3   4.1 +/− 1.31.9 +/− 0.3 3 BONE Bmp8a M97017 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   0 +/−0 5.6 +/− 1.2 MORPHO- GENETIC PROT. 8A TPA TPAR1 S74318 −1.8 +/− 0.1   0+/− 0 0 +/− 0 0 +/− 0   2.2 +/− 0.2   9 +/− 1.9 REPRESSED GENE 1SECRETED Sfrp3 U91905 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   9.5 +/− 1   2.2+/− 0.8 FRIZZLED- RELATED PROT. 3 OSTEOPRO- Tnfrsf11b U94331 0 +/− 0 0+/− 0 0 +/− 0 0 +/− 0   5.2 +/− 0.6 0 +/− 0 TEGERIN FOLLI- Fst Z29532 0+/− 0 2.4 +/− 0.3 0 +/− 0 0 +/− 0   4.2 +/− 0.1 0 +/− 0 STATIN GROWTHGdf1 M62301 0 +/− 0 0 +/− 0 0 +/− 0  −4.7 +/− 0    0 +/− 0 0 +/− 0DIFFEREN. FACT. 1 Extracellular Matrix Proteins TENASCIN Tnc X56304 0+/− 0 6.6 +/− 1.6 14.4 +/− 1.7  34.5 +/− 13    91.6 +/− 22.7 68.9 +/−7.6  C SECRETED Spp1 J04806 2.4 +/− 0.9 3.4 +/− 1.4 6 +/− 1 15.7 +/−10.7   46.2 +/− 8.7  98.3 +/− 5.1  PHOSPHO- PROT. 1 BIGLYCAN Bgn X539281.8 +/− 0.3 2.8 +/− 0.5 4.2 +/− 0.1 5.8 +/− 1    11.6 +/− 1.3  12.1 +/−1.4  PROCOLL., Col5a1 AB009993 0 +/− 0 0 +/− 0 3.1 +/− 0.9 9 +/− 2.217.1 +/− 3.2  15.5 +/− 1.5  TYPE V, ALPHA 1 CHON- Cspg2 D16263 2.4 +/−1   3.1 +/− 0.6 4.4 +/− 0.5 5.4 +/− 0.4   5.1 +/− 1.2 2.4 +/− 0.3DROITIN SULFATE PROTEO- GLYCAN 2 PROCOLL., Col5a2 L02918 0 +/− 0 2.4 +/−0.3 3.6 +/− 0.5 7 +/− 0   17.2 +/− 1   18.3 +/− 0.4  TYPE V, ALPHA 2AGGRECAN Agc L07049 0 +/− 0 0 +/− 0 0 +/− 0 4.8 +/− 2    27.6 +/− 3.4 4.7 +/− 0.8 FIBRO- Fn1 M18194 0 +/− 0 3.1 +/− 0.2   3 +/− 0.4 4.5 +/−0.4   7.8 +/− 0.5 6.1 +/− 0.4 NECTIN 1 ALPHA-1 Col3a1 M18933 0 +/− 0 2.3+/− 0.3 2.2 +/− 0.3 5 +/− 0.2  13 +/− 1.2 7.9 +/− 0.7 TYPE-III COLLAGENTHROMBO- Thbs1 M87276   3 +/− 0.7 3.8 +/− 0.8 3.9 +/− 1.2 9.5 +/− 3.4  27.2 +/− 6.4  8.5 +/− 2   SPONDIN 1 PROCOLL., Col12a1 U25652 0.5 +/− 1.4  2 +/− 0.3 3.9 +/− 0.4 7.9 +/− 2.5   29.4 +/− 7.5  12.1 +/− 1.3  TYPEXII, ALPHA 1 PROCOLL., Col6a2 X65582 0 +/− 0 0 +/− 0 0 +/− 0 5.6 +/−0    14.1 +/− 2.6  9.7 +/− 0.5 TYPE VI, ALPHA 2 COL8A1 Col8a1 X66977 0+/− 0 2.4 +/− 0.2 1.8 +/− 0.1 6.8 +/− 1.4   23.4 +/− 3.7  8.1 +/− 3.1LUMICAN Lum AF013262 0 +/− 0 0 +/− 0 0 +/− 0 2.9 +/− 0.5   8.5 +/− 0.87.7 +/− 1   COL11A2 Col11a2 AF100956 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0  23.7 +/− 0.2  24.2 +/− 9   PROCOLL., Col11a1 D38162 0 +/− 0 0 +/− 0 0+/− 0 0 +/− 0   79.8 +/− 1.6  49.7 +/− 3.7  TYPE XI, ALPHA 1 INTEGRINIbsp L20232 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   237.8 +/− 9    174.1 +/−17   BINDING SIALOPROT. BONE GLA. Bglap1 L24431 0 +/− 0 0 +/− 0 −4.1 +/−1    0 +/− 0   14.9 +/− 4.7  59.6 +/− 3.8  PROT. 1 PROCOLL., Col2a1M65161 0 +/− 0 0 +/− 0 −1.8 +/− 0.1   0 +/− 0   168.1 +/− 24   28.9 +/−3   TYPE II, ALPHA 1 PROCOLL., Col6a1 Z18271 0 +/− 0 0 +/− 0 1.7 +/− 0  3.4 +/− 0.1     5 +/− 0.3   4 +/− 0.4 TYPE VI, ALPHA 1 PROCOLL., Col10a1Z21610 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   45.1 +/− 29.9 5.6 +/− 3.2 TYPEX, ALPHA 1 CARTILAGE Comp AF033530 0 +/− 0 2.2 +/− 0.4 0 +/− 0 2.3 +/−0.6   10.8 +/− 0.7  2.8 +/− 0.4 OLIGO- MERIC MATRIX PROT. CARTILAGECrtl1 AF098460 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   14.9 +/− 1.1  0 +/− 0LINK PROT. 1 PROCOLL., Col14a1 AJ131395 0 +/− 0 0 +/− 0 0 +/− 0 0 +/−0   4.1 +/− 0.8 2.1 +/− 0.3 TYPE XIV, ALPHA 1 PROCOLL., Col9a1 D17511 0+/− 0 0 +/− 0 0 +/− 0 0 +/− 0    14 +/− 0.7 0 +/− 0 TYPE IX, ALPHA 1PROCOLL., Col15a1 D17546 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   6.9 +/− 0.63.9 +/− 0.7 TYPE XV BONE GLA. Bglap-rs1 L24430 0 +/− 0 0 +/− 0 0 +/− 0 0+/− 0   0 +/− 0 77.8 +/− 18.8 PROT., RELATED SEQ. 1 EXTRACELL- Ecm1L33416 0 +/− 0 2.4 +/− 0.2 2.6 +/− 0.2 3 +/− 0.4 3.2 +/− 0.6 5.1 +/− 0.2ULAR MATRIX PROT. 1 ELASTIN Eln U08210 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0  0 +/− 0 4.2 +/− 1.8 ALPHA 3 Col9a3 X91012 0 +/− 0 0 +/− 0 0 +/− 0 0 +/−0   9.8 +/− 0.8 0 +/− 0 TYPE IX COLLAGEN. PROCOLL., Col9a2 Z22923 0 +/−0 0 +/− 0 0 +/− 0 0 +/− 0   4.4 +/− 2.1 0 +/− 0 TYPE IX, ALPHA 2Extracellular Proteins NEURO- Nbl1 D50263 0 +/− 0 0 +/− 0 0 +/− 0 0 +/−0     6 +/− 3.7 5.5 +/− 1.1 BLASTOMA, SUPP. OF TUMORIGEN. 1 IGF Igfbp4X76066 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   7.1 +/− 1.2 5.4 +/− 0.4 BINDINGPROT. 4 APOLIPO- Apoe D00466 0 +/− 0 1.8 +/− 0.4 2.4 +/− 0.1 2.7 +/−0.1   3.8 +/− 0.2 4.8 +/− 0.3 PROT. E IGF Igfbp3 X81581 0 +/− 0 0 +/− 00 +/− 0 0 +/− 0     5 +/− 0.4 3.2 +/− 1   BINDING PROT. 3 VITRO- VtnM77123 −2.1 +/− 0.2   −4.2 +/− 1    −2.3 +/− 0.3   0 +/− 0   0 +/− 0 0+/− 0 NECTIN Intracellular Proteins CELL DIV. Cdc2a M38724 1.6 +/− 0.67.2 +/− 1.1 10.6 +/− 0.9  13.4 +/− 3.9   12.1 +/− 1.6    4 +/− 0.2 CYCLE2 HOMOLOG A LYSYL Lox M65142 0 +/− 0 5.3 +/− 0.7 8.9 +/− 1   12.6 +/−0.6   22.8 +/− 1.3  15.5 +/− 0.9  OXIDASE PROCOLL- Plod2 AF080572 0 +/−0 2.9 +/− 0.4 6.2 +/− 2.6 15.2 +/− 4.4   13.5 +/− 1.8  11.6 +/− 1.7 LYS., 2-OXOGLUT. 5-DIOXY- GEN. 2 ALK. PHOS- Akp2 J02980 0 +/− 0 0 +/− 05 +/− 1 6.1 +/− 3.6   32.6 +/− 2.9  18.5 +/− 3.8  PHATASE 2, LIVER HEMEHmox1 X13356 1.9 +/− 0.3   4 +/− 1.5 4.5 +/− 1.2 7.3 +/− 2.3   8.2 +/−0.3 7.6 +/− 1   OXYGENASE (DECYCL- ING) 1 PROCOLL- Plod3 AF046783 0 +/−0 3.7 +/− 0.6 4.6 +/− 0.2 5.1 +/− 0.5   8.5 +/− 0.7 3.8 +/− 0.9 LYS., 2-OXOGLUT. 5- DIOXY- GEN. 3 PHOSPHO- Pla2g4 M72394 0 +/− 0 2.6 +/− 0.5 3.9+/− 0.1 6.9 +/− 1.8   7.2 +/− 0.6 4.4 +/− 0.1 LIPASE A2, GROUP 4 ATPASE.Tcirg1 AB022322 0 +/− 0 0 +/− 0 3.1 +/− 0.8 0 +/− 0     7 +/− 1.4 27.8+/− 2.4  H+ TRANSPORT- ING, LY- SOSOMAL I LYSYL Loxl2 AF117951 0 +/− 0 0+/− 0 0 +/− 0 7.2 +/− 0.6   7.7 +/− 0.8 2.1 +/− 0.4 OXIDASE- LIKE PROT.2 PROS- Ptgs2 M64291 0 +/− 0 2.5 +/− 0.3 2.3 +/− 0   8.9 +/− 3.4   5.5+/− 1.2 −0.3 +/− 1.6   TAGLAN.- ENDOPEROX. SYNTHASE 2 CREATINE CkbM74149 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   4.6 +/− 0.6 28.6 +/− 2  KINASE, BRAIN CALRETIC- Calr X14926 0 +/− 0 2.9 +/− 0.2   3 +/− 0.3 4.1+/− 0.6   5.5 +/− 0.2 3.9 +/− 0.3 ULIN BCL2- Bax L22472 0 +/− 0 2.5 +/−0.4 2.1 +/− 0.2 0 +/− 0   4.9 +/− 0.8 0 +/− 0 ASSOCI- ATED X PROT.CARBONIC Car2 M81022 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   0.3 +/− 1.4 13.8+/− 3.7  ANHYDRASE 2 LYSYL Loxl U79144 0 +/− 0   2 +/− 0.1 0 +/− 0 3.5+/− 0.1   4.6 +/− 0.6 3.4 +/− 0.3 OXIDASE- LIKE FATTY Fasn X13135 0 +/−0 −1.5 +/− 2.6   −4.4 +/− 0.6   −3.3 +/− 2.4    −3.9 +/− 1.2   −0.2 +/−2.3   ACID SYNTHASE Proteases TISSUE Timp M17243 1.1 +/− 2   12.8 +/−3.2  25.4 +/− 7.6  48.1 +/− 11.6   100.3 +/− 11    56 +/− 3.5 INHIB. OFMETALLO- PROT. SERINE Spi2-2 M64086 0 +/− 0 6.8 +/− 1.2 7.4 +/− 0.8 8.3+/− 2.5   7.7 +/− 1.3 2.4 +/− 1.1 PROTEASE INHIB. 2-2 BONE Bmp1 L24755 0+/− 0 0 +/− 0 2.9 +/− 0.5 6.8 +/− 1.7    23 +/− 4.1 18.1 +/− 0.3 MORPHO- GENETIC PROT. 1 MATRIX Mmp14 U54984 0 +/− 0 2.8 +/− 0.4 2.7 +/−0   7 +/− 1.3 23.1 +/− 3.8  18.1 +/− 4.6  METALLO- PROT. 14 CATHEPSINCtsk X94444 0 +/− 0 0 +/− 0 0 +/− 0 6.1 +/− 4    11.3 +/− 3.1   47 +/−1.6 K MATRIX Mmp9 Z27231 0 +/− 0 0 +/− 0 0 +/− 0 20 +/− 16.8 16.3 +/−12.3 221.5 +/− 18   METALLO- PROT. 9 PROCOLL. Pcolce AB008548 0 +/− 0 0+/− 0 0 +/− 0 3.3 +/− 0.5     7 +/− 1.2 6.7 +/− 0.8 C-PROT. ENHANCERPROT. PLASMINO- Plat J03520 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   5.3 +/−1.3 4.6 +/− 0.6 GEN ACT., TISSUE MATRIX Mmp2 M84324 −2.1 +/− 0.3   −1.8+/− 0.1   0.1 +/− 1.7 2.7 +/− 0.4   8.1 +/− 1.1 7.2 +/− 0.6 METALLO-PROT. 2 UROKINASE Plaur X62700 1.7 +/− 0.3 3.1 +/− 0.5 0 +/− 0 4.4 +/−1    7.8 +/− 0.7 2.3 +/− 0.4 PLASMINO- GEN ACT. RECEPT. MATRIX Mmp 13X66473 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   19.3 +/− 2.5  144.8 +/− 24  METALLO- PROT. 13 PLASMINO- Serpine 1 M33960 0 +/− 0 2.9 +/− 0.7 2.8 +/−0.3 5 +/− 1.3 3.2 +/− 0.5 0 +/− 0 GEN ACT. INHIB., TYPE I TISSUE Timp2X62622 0 +/− 0 1.7 +/− 0.1 1.8 +/− 0   2.6 +/− 0.4   4.7 +/− 0.9 3.8 +/−0.5 INHIB. OF METALLO- PROT. 2 Receptors TGF BETA Tgfbi L19932 2.8 +/−0.7 6 +/− 2 5.6 +/− 0.7 7.8 +/− 0.7   5.3 +/− 1     2 +/− 0.4 INDUCED,68 KDA PARATHY- Pthr X78936 0 +/− 0 0 +/− 0   3 +/− 0.1 6 +/− 1.9 57.4+/− 1.3  25.5 +/− 1.1  ROID HORMONE RECEPT. PTP, Ptprd D13903 0 +/− 0 0+/− 0 0 +/− 0 1.6 +/− 0.1   6.6 +/− 0.4 8.7 +/− 2.2 RECEPT. TYPE, D IL-4II4ra M29854 0 +/− 0 4.8 +/− 1.4 2.9 +/− 0.1 0 +/− 0   8.1 +/− 0.7 0 +/−0 RECEPT., ALPHA FIBROBL. Fgfr2 M86441 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0  15.3 +/− 2.5  7.9 +/− 1.3 GROWTH FACT. RECEPT. 2 COLONY Csf1r X68932 1.8+/− 0.5 3.2 +/− 0.4 3.3 +/− 0.5 4.1 +/− 0.6   3.5 +/− 0.6 10.9 +/− 0.9 STIM. FACT. 1 RECEPT. ACTIVIN A Acvr1 L15436 0 +/− 0 0 +/− 0 1.9 +/− 0.22.7 +/− 0.3   4.6 +/− 0.1 0 +/− 0 RECEPT., TYPE 1 COLONY Csf3r M58288 0+/− 0 0 +/− 0 0 +/− 0 0 +/− 0   0 +/− 0 4.9 +/− 0.9 STIM. FACT. 3RECEPT. COLONY Csf2ra M85078 0 +/− 0 2.6 +/− 0.7 3.3 +/− 0.3 0 +/− 0  4.8 +/− 0.8 3.9 +/− 0.4 STIM. FACT. 2 RECEPT., ALPHA TGF BETA Tgfbr2S69114 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   0 +/− 0 4.7 +/− 1   RECEPT. IISignal Transduction C-SRC Csk U05247 0 +/− 0 2.6 +/− 0.3 0 +/− 0 2.9 +/−0.1   4.9 +/− 0.4 3.6 +/− 0.2 TYROSINE KINASE Transcription Factors MADMadh6 AF010133 6.7 +/− 3   8.1 +/− 1.7 9.9 +/− 2.3 4.6 +/− 0.9   7.7 +/−2.9 5.5 +/− 0.5 HOMOLOG 6 INHIB. OF Idb1 M31885 3.6 +/− 0.7 8.1 +/− 1.97.6 +/− 0.8 4.9 +/− 1.9   4.4 +/− 1.7 4.9 +/− 0.6 DNA BINDING 1 INHIB.OF Idb2 M69293 2.4 +/− 0.6 4.5 +/− 0.6 5.7 +/− 1.4 4.8 +/− 0.5   11.9+/− 3.2  5.7 +/− 0.7 DNA BINDING 2 RUNT Runx2 D14636 0 +/− 0 2.6 +/− 0.53.8 +/− 0.2 8.9 +/− 2.7   15.8 +/− 1.3  20.1 +/− 4.9  RELATED TRANSCRIP.FACT. 2 JUN-B Junb J03236 0.9 +/− 1.7 4.4 +/− 0.5 2.7 +/− 0   3.6 +/−1.2   5.1 +/− 1   2.3 +/− 0.4 ONCOGENE SCLERAXIS Scx S78079 0 +/− 0 3.8+/− 1.9 6.9 +/− 3.8 0 +/− 0   19.4 +/− 6   0 +/− 0 SIG. Stat1 U06924 0+/− 0 2.2 +/− 0.3 3.5 +/− 0.9 4.7 +/− 0.3   2.7 +/− 0.1 5.2 +/− 3.2TRANS. AND ACT. OF TRANS- CRIP. 1 DISTAL- Dlx5 U67840 0 +/− 0 0 +/− 0 0+/− 0 0 +/− 0   8.5 +/− 1   7.5 +/− 1   LESS HOMEOBOX 5 NUC. FACT.Nfatc1 AF049606 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   2.7 +/− 0.8 5.2 +/−0.8 ACTIV. T- CELLS, CYTOPLAS. 1 MAD Madh2 U60530 0 +/− 0   2 +/− 0.32.5 +/− 0.2 0 +/− 0   4.5 +/− 0.7 0 +/− 0 HOMOLOG 2 SLUG Slugh U79550 0+/− 0 0 +/− 0 0 +/− 0 0 +/− 0   4.4 +/− 3.1 0 +/− 0 INHIB. OF Idb4X75018 2.8 +/− 1.4 3.5 +/− 0.6 3.7 +/− 1.2 0 +/− 0   1.7 +/− 0.2   6 +/−0.3 DNA BINDING 4

[0361] TABLE 6 BMP-2-induced changes in the expression of known genesnot explicitly associated with bone or cartilage metabolism*. Gene TitleSymbol GenBank Day 1 Day 2 Day 3 Day 4 Day 7 Day 14 Cell SurfaceProteins CD68 Cd68 X68273 2.2 +/− 0.5 3.2 +/− 0.5 3.8 +/− 0.6 5.1 +/−0.6 6.5 +/− 1.1 15.8 +/− 0.5  ANTIGEN FIBROBL. Fap Y10007 0 +/− 0 0 +/−0 0 +/− 0 2.3 +/− 0.1 5.6 +/− 0.7 10.9 +/− 0.4  ACTIVA- TION PROT. CD9ANTI- Cd9 L08115 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 3.5 +/− 0.3 4.1 +/− 0.1GEN HEPATIC Lipc X58426 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.5 +/−0.9 LIPASE SELECTIN, Selpl X91144 0 +/− 0 2.3 +/− 0.2 2.5 +/− 0.3 3.2+/− 0.4 3.2 +/− 0.3 7.2 +/− 0.6 PLATELET (P- SELECTIN) LIGAND EPHRIN B1Efnbl Z48781 0 +/− 0 0 +/− 0 1.6 +/− 0.1 0 +/− 0 5.9 +/− 1   3.4 +/− 1.2Cytokines MONO. Scya7 S71251 4.1 +/− 0.7 9.3 +/− 1.7 5.7 +/− 2.3 8.1 +/−2.2 6.6 +/− 1.5 0 +/− 0 CHEMO- TACTIC PROT.-3 SMALL Scya12 U50712 1.9+/− 0.1 4.1 +/− 2.1 5.6 +/− 0.8 3.8 +/− 0.1 10.7 +/− 2   0 +/− 0INDUCIB. CYTOKINE A12 SECRETED Sfrpl U88566 0 +/− 0 2.8 +/− 0.9 5.9 +/−0.5 11.4 +/− 5.9  9.3 +/− 1.8 2.5 +/− 0.5 FRIZZLED- RELATED PROT. 1SMALL Scyb9 M34815 0 +/− 0 0 +/− 0 3.4 +/− 0.5 5.2 +/− 0.4 3.6 +/− 0.6  7 +/− 7.7 INDUCIB. CYTOKINE B MEMBER 9 VASCULAR Vegftb U48800 0 +/− 0−2.3 +/− 1    0 +/− 0 −9.6 +/− 9.3   −7.8 +/− 3.9   −2.7 +/− 0.4   ENDO-THELIAL GROWTH FACT. B SMALL Scya11 U40672 −4.1 +/− 2    −3.4 +/− 0.4  0 +/− 0 −1.5 +/− 0.3   −2.6 +/− 1    −2.4 +/− 0.5   INDUCIB. CYTOKINEA11 Extracellular Proteins LIPOCOR- Anxa1 M24554   2 +/− 0.5 2.4 +/− 0.22.7 +/− 0.6 3.8 +/− 0.6 4.5 +/− 0.8   5 +/− 0.2 TIN 1 SECRETED Sfrp4AF117709 0 +/− 0 −1.3 +/− 0.1   0 +/− 0 0 +/− 0 0 +/− 0 12.7 +/− 0.8 FRIZZLED- RELATED PROT. 4 SUPEROX. Sod3 D50856 0 +/− 0   4 +/− 1.1 3.8+/− 0.1 3.6 +/− 1   4.4 +/− 0.8 0 +/− 0 DISMUTASE 3, EX- TRACELL.ANNEXIN Anxa4 U72941 0 +/− 0   1 +/− 1.8 2.1 +/− 0.2 2.9 +/− 0.4 3.8 +/−0.9 4.2 +/− 0.1 A4 AMYLOID App U84012 0 +/− 0 1.8 +/− 0.2 1.6 +/− 0.22.5 +/− 0     4 +/− 0.6 2.7 +/− 0.4 BETA (A4) PRECUR. PROT.Intracellular Proteins PLASTIN Pls2 D37837 0 +/− 0 4.5 +/− 0.8 4.3 +/−0.4 5.2 +/− 0.3 8.1 +/− 0.9 11.4 +/− 1.1  2, L CYSTEINE- Csrp2 AF0372080 +/− 0 3.8 +/− 0.3 8.4 +/− 1.9 15.8 +/− 3.4  25.8 +/− 7.5  6.5 +/− 0.8RICH PROT. 2 FGF Fgfrp U04204 0 +/− 0 3.7 +/− 0.7   4 +/− 0.9 5.7 +/−1.4 5.6 +/− 0.7 5.9 +/− 0.8 REGULATED PROT. CARBONYL Cbr2 D26123 1.6 +/−0.4 4.6 +/− 0.4 6.8 +/− 0.5 5.1 +/− 0.2 2.1 +/− 0.1 1.9 +/− 0.2REDUCTASE 2 ENDO- Grp58 M73329 0 +/− 0 2.8 +/− 0.2 2.8 +/− 0.3 4.8 +/−0.8   7 +/− 1.6 4.3 +/− 0.3 PLASMIC RETICULUM PROT. CYCLIN D1 Cyl-1S78355 0 +/− 0 3.2 +/− 0.1 4.5 +/− 0.2 0 +/− 0 7.2 +/− 0.6 6.4 +/− 0.6TRANS- Abcb2 U60019 0 +/− 0 1.8 +/− 0.4 4.2 +/− 0.2 3.7 +/− 0.9 4.9 +/−0.2 5.3 +/− 2.9 PORTER 1, ATP BINDING CASSETTE 2′-5′ Oas1a X04958 1.8+/− 0.2 2.8 +/− 0.6 4.3 +/− 0.7 5.8 +/− 1.2 5.1 +/− 0.4 3.7 +/− 0.5OLIGOA- DENYLATE SYNTHE- TASE 1A CALCIUM S100a10 M16465 1.9 +/− 0.5 2.5+/− 0.1 2.8 +/− 0.5 3.4 +/− 0.2 4.4 +/− 0.7 4.2 +/− 0.3 BIND. PROT. A11(CAL- GIZZARIN) MYOSIN Myla M19436 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   8+/− 2.5 5.5 +/− 1.1 LIGHT CHAIN, ALKALI, ATRIA RETINOL Rbp1 X60367 0 +/−0 0 +/− 0 0 +/− 0 4.1 +/− 0.9 7.1 +/− 0.8 2.4 +/− 0.1 BINDING PROT. 1,CELLULAR CYCLIN A2 Ccha2 Z26580 0 +/− 0 3.1 +/− 0.5 3.6 +/− 0.7 4.8 +/−0.3 5.7 +/− 0.3 1.9 +/− 0.2 PROCOLL- Plod1 AF046782 0 +/− 0 0 +/− 0 0+/− 0 0 +/− 0 5.2 +/− 1.1 3.4 +/− 0.4 LYS., 2- OXOGLUT. 5-DIOXY- GEN. 1GALACTO- B4galt1 J03880 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0   8 +/− 1.8 0+/− 0 SYLTRANS- FERASE, POLYPEP. 1 RHO, GDP Arhgdib L07918 0 +/− 0   4+/− 0.4 3.1 +/− 0.3 3.3 +/− 0.5 4.4 +/− 0.3 3.8 +/− 1.2 DISSOCIA- TIONINHIB. BETA STEROL O- Soat1 L42293 0 +/− 0 2.5 +/− 0.6 2.2 +/− 0.2 3.6+/− 0.2 5.4 +/− 0.9 2.9 +/− 0.7 ACYL- TRANS- FERASE 1 CYCLIN D2 Ccnd2M83749 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.2 +/− 0.1 3.7 +/− 0.1 RAT PRO-Psmb9 S59862 0 +/− 0 2.8 +/− 0.5 3.3 +/− 0.4 5.5 +/− 0.9 0 +/− 0 3.8 +/−4.1 TEASOME HOMOLOG LYMPHO- Lcp2 U20159 0 +/− 0 2.4 +/− 0.4 2.5 +/− 0.33.1 +/− 0.7 3.2 +/− 0.6 4.8 +/− 0.2 CYTE CYTOSOLIC PROT. 2 TRANS- Abcb3U60087 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.7 +/− 2.1 PORTER 2, ATPBINDING CASSETTE CAPPING Capg X54511 0 +/− 0 2.6 +/− 0.2 2.6 +/− 0.4   3+/− 0.1 3.8 +/− 0.4 4.7 +/− 1   PROT., GELSOLIN- LIKE CYCLIN Ccnb1-rs1X58708  0+/−0   2.4 +/− 0.2 3.1 +/− 0.2 3.9 +/− 0.4 4.1 +/− 0.1 1.7 +/−0.2 B1, RELATED SEQ. 1 CYCLIN B2 Ccnb2 X66032 0 +/− 0 3.6 +/− 0.5 2.7+/− 0.6 4.4 +/− 0.7 2.9 +/− 0.2 2.2 +/− 0.4 HISTONE Hdac1 X98207 0 +/− 00 +/− 0 3.2 +/− 0.2 0 +/− 0 7.3 +/− 0.7 3.2 +/− 0.3 DEACETYL- ASE 1Proteases MATRIX Mmp23 AF085742 0 +/− 0 0 +/− 0 0 +/− 0 11.2 +/− 1  39.9 +/− 3   15.7 +/− 0.6  METALLO- PROT. 23 CASPASE 6 Casp6 Y13087 0+/− 0 0 +/− 0 2.8 +/− 1.3 4.9 +/− 2.1 7.6 +/− 1.6 7.7 +/− 0.9 CATHEPSINCtsh U06119 0 +/− 0 2.1 +/− 0.4 2.3 +/− 0.2 3.6 +/− 0.2 5.8 +/− 0.8 4.4+/− 0.6 H CATHEPSIN Ctss AF03854 1.8 +/− 0.3 2.8 +/− 0.5 3.2 +/− 0.4 4+/− 0 3.8 +/− 0.5 5.4 +/− 1   S PROTEO- Psmb8 U22032 0 +/− 0 2.9 +/− 0.43.5 +/− 0.2 3.7 +/− 0.6 3.4 +/− 0.3 6.3 +/− 4.3 SOME SUBUNIT, BETA TYPE8 SERINE Serpine2 X70296 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 3.4 +/− 0.3 8.9+/− 1.2 PROTEASE INHIB. 4 Receptors IL-2 II2rg L20048 0 +/− 0 3.9 +/−0.7 4.7 +/− 0.2 5.6 +/− 0.5 7.9 +/− 0.8 5.3 +/− 0.9 RECEPT., GAMMA CHAINCYTOKINE Crlf1 AB04003I  3 +/− 1.1 7.6 +/− 1   7.2 +/− 2.9 14.7 +/− 6.4 8.8 +/− 4   2.1 +/− 0.5 RECEPT.- LIKE FACT. 1 FC Fcgr1 X70980 2.7 +/−0.5 7.6 +/− 2.7 7.3 +/− 0.6 6.7 +/− 1.2 4.8 +/− 1.1 0 +/− 0 RECEPT.,IGG, HIGH AFFINITY 1 PTP, Ptprc M14342 2.5 +/− 0.5 3.4 +/− 0.4 4.3 +/−1.7 5.2 +/− 0.9 3.3 +/− 0.8 6.8 +/− 0.8 RECEPT. TYPE, C CHEMOKINE Cmkbr2U51717 2.9 +/− 1   6.1 +/− 0.8 5.1 +/− 1.3 4.2 +/− 0.4 3.4 +/− 0.6 3.6+/− 0.4 (C-C) RECEPT. 2 TNF Tnfrsf1a L26349 1.4 +/− 0.3 2.7 +/− 0.2 1.9+/− 0   2.8 +/− 0.1 4.1 +/− 0.2   4 +/− 0.1 RECEPT. SUPER- FAMILY,MEMBER 1A CHEMOKINE Cmkbr1 U29678 3.4 +/− 1.6 4.9 +/− 1   2.4 +/− 0.72.8 +/− 0.2 1.9 +/− 0.2 13.3 +/− 0.6  (C-C) RECEPT. 1 PDGF Pdgfrb X043670 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.6 +/− 1.5 4.8 +/− 1   RECEPT., BETAPOLY- PEPTIDE PTP. Ptprs X82288 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.1 +/−0.7 5.4 +/− 0.5 RECEPT. TYPE, S FRIZZLED- Fzd1 AF054623 0 +/− 0 0 +/− 00 +/− 0 0 +/− 0 5 +/− 1 1.4 +/− 0.4 1 ANGIO- Agtrl1 AJ007612 0 +/− 0 0+/− 0 0 +/− 0 0 +/− 0 4.2 +/− 0.6 2.9 +/− 0.1 TENSIN RECEPT.- LIKE 1LEUKEMIA Lifr D17444 0 +/− 0 1.2 +/− 0.1 0 +/− 0 0 +/− 0 3.2 +/− 0.3 9.9+/− 1.3 INHIB. Y FACT. RECEPT. FC Fcgr3 M14215 0 +/− 0 3.6 +/− 0.4 3.4+/− 0.3 3.6 +/− 0   4.2 +/− 0.4 0 +/− 0 RECEPT., IGG, LOW AFFINITY IIIPTP. Ptpra M36033 0 +/− 0 0 +/− 0 0 +/− 0 2.9 +/− 0.1 3.9 +/− 0.7   4+/− 0.4 RECEPT. TYPE, A CHEMOKINE Cmkbr5 U47036 2.7 +/− 1   4.8 +/− 1.92.6 +/− 0.1 3.5 +/− 0.2 3.2 +/− 0.2 1.5 +/− 0.2 (C-C) RECEPT. 5 EPHEpha2 X76010 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 5.1 +/− 0.9   3 +/− 0.2RECEPT. A2 EPH Ephb3 Z49086 0 +/− 0 0 +/− 0 0 +/− 0 2.5 +/− 1   7.1 +/−1.5 2.9 +/− 0.2 RECEPT. B3 RETINOID Rxrg X66225 0 +/− 0 0 +/− 0 0 +/− 0−4.2 +/− 3.1   −4.5 +/− 0.4   −4.6 +/− 2.5   X RECEPT. GAMMA SignalTransduction APLYSIA Arhc X80638 0 +/− 0 0 +/− 0 3.5 +/− 0.4 5.7 +/− 0.3  7 +/− 0.8 7.6 +/− 0.2 RAS- RELATED HOMOLOG 9 FYN Fyn M27266 0 +/− 0 0+/− 0 1.5 +/− 0.4 2.2 +/− 0.1 4.2 +/− 0.5 4.4 +/− 0.7 PROTO- ONCOGENERAS P21 Rasa3 U20238 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.4 +/− 0.4 4.7 +/−0.5 PROT. ACT. 3 DOWN- Dok1 U78818 0 +/− 0 1.7 +/− 0.5 2.7 +/− 1.1 4.5+/− 1.4 5.4 +/− 1.5 3.3 +/− 0.1 STREAM OF TYROSINE KINASE 1 MITOGEN-Map4k4 U88984 0 +/− 0   2 +/− 0.3 2.6 +/− 0.3 3.1 +/− 0.1 5.2 +/− 0.54.9 +/− 0.7 ACTIVATED PROT. (KINASE)4 VAV Vav X64361 0 +/− 0 4.3 +/− 0.43.2 +/− 0.2   4 +/− 0.4 2.3 +/− 0.2 0 +/− 0 ONCOGENE HEMATO. Hcls1X84797 2.7 +/− 1.3 5.6 +/− 1.5 4.2 +/− 1.3 3.2 +/− 0.6   4 +/− 0.9 3.1+/− 0.5 CELL SPECIFIC LYN SUBSTR. 1 REGULATOR Rgs2 AF215668 0 +/− 0 1.5+/− 0.4 2.9 +/− 0.9 3.2 +/− 0.2 2.8 +/− 0.6 5.6 +/− 0.7 OF G- PROT. SIG.2 ANNEXIN Anxa8 AJ002390 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 8.3 +/− 1.6 3.8+/− 0.2 A8 CYCLIN- Cdk4 L01640 0 +/− 0 2.4 +/− 0.2 2.5 +/− 0   3.4 +/−0.7 5.2 +/− 0.7 3.5 +/− 0.1 DEPENDENT KINASE 4 INOSITOL Inpp5d U52044 0+/− 0 1.9 +/− 0.3 1.9 +/− 0.5 0 +/− 0 3.7 +/− 0.8 4.3 +/− 0.4 POLY-PHOS.- 5-PHOS- PHATASE CYTO. Cish3 U88328 0 +/− 0 3.6 +/− 0.7 0 +/− 0 0+/− 0 5.6 +/− 1.5 1.8 +/− 0.2 INDUCIB. SH2-CON- TAINING PROT. 3 FELINEFes X12616 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 7 +/− 1 0 +/− 0 SARCOMAONCOGENE PTP. NON- Ptpn12 X86781 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 3.2 +/−1.1 4.9 +/− 0.5 RECEPT. TYPE 12 APLYSIA Arhb X99963 0 +/− 0 0 +/− 0 0+/− 0 0 +/− 0 3.5 +/− 0.5   4 +/− 0.4 RAS- RELATED HOMOLOG B StructuralProteins TROPONIN Tnnt2 L47570 0 +/− 0 0 +/− 0 −1.3 +/− 0.1     4 +/−2.7 12.4 +/− 5.2  3.4 +/− 1.6 T2, CARDIAC NESTIN Nes AF076623 0 +/− 0 0+/− 0 0 +/− 0 0 +/− 0 6.1 +/− 1.2 0 +/− 0 CORONIN, Coro1a AF143955 1.8+/− 0.4 4.1 +/− 0.8 2.9 +/− 0   3.3 +/− 0.4 3.3 +/− 0.1 3.7 +/− 1.1ACTIN BINDING PROT. 1A MYOSIN Myhca M76601 0 +/− 0 −3.9 +/− 3.9   0 +/−0 −9.1 +/− 9.4   −8.9 +/− 6.3   −6.6 +/− 6    HEAVY CHAIN, CARDIACMUSCLE Transcription Factors MYOGENIN Myog D90156 0 +/− 0 6.9 +/− 5.16.6 +/− 2.8 17.2 +/− 13.6 15.8 +/− 10.6 0 +/− 0 MYOGENIC Myod1 M849186.4 +/− 0.9 7.5 +/− 3.1 5.3 +/− 3.6 0 +/− 0   8 +/− 3.7 0 +/− 0DIFFEREN. 1 SFFV Sfpi1 X17463 0 +/− 0 2.1 +/− 0.6 4.2 +/− 0   2.8 +/−0.3 4.4 +/− 1   8 +/− 1 PROVIRAL INTEGRA- TION 1 ELK3, ETS Elk3 Z32815 0+/− 0 2.4 +/− 0.3 2.7 +/− 0.5 0 +/− 0 6.4 +/− 0.5 4.6 +/− 0.5 ONCOGENEFAMILY INS-1 Foxm1 U83112 1.6 +/− 0.5 2.6 +/− 0.5 0 +/− 0 2.4 +/− 0.43.1 +/− 0.3 4.4 +/− 1.8 WINGED HELIX INTERFER- Irf1 M21065 0 +/− 0 0 +/−0 0 +/− 0 0 +/− 0 0 +/− 0 5.4 +/− 2.4 ON REG. FACT. 1 T-CELL Tal1 U015304.1 +/− 1.7 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 0 +/− 0 ACUTE LYMPHO- CYTICLEUKEMIA 1 PEROX. Pparg U09138 0 +/− 0 0 +/− 0 3.3 +/− 0.4 0 +/− 0 0 +/−0 4.9 +/− 0.4 PROLIF. ACTIV. RECEPT. GAMMA NFKB Nfkbia U36277 0 +/− 0 0+/− 0 0 +/− 0 0 +/− 0 0 +/− 0 4.3 +/− 0.4 INHIB., ALPHA # theintersection of searches 1 AND 2. If no records were returned in thethird search, then it was determined that there is no explicitassociation between the gene and bone or cartilage metabolism.

[0362] TABLE 7 A correlative analysis of genes having expressionprofiles similar to selected marker genes. Similar to Similar to Similarto Similar to Cyr61 Col2a1 Runx2 Ctsk Genes from Table 5 Scya8 CompPcolce Tcirg1 Cspg2 Crtl1 Col5a1 Itgb3 Cyr61 Col14a1 Lum Ctsk Cdc2aCol9a1 Nfatc1 Sdf1 Agc Apoe Spp1 Pdgfa Ptprd Bglap-rs1 Mdk Runx2 Bglap1Col2a1 Cdh11 Ckb Fgfr2 Spp1 Car2 Slugh Col5a2 Bmp8a Sfrp3 Bmp1 Tgfbr2Tnfrsf11b Csf3r TPAR1 col8a1 Tgfbr2 Gja1 Pthr Itgav Mmp13 moucol9a3 Sdc1Mmp9 Col10a1 Bgn Col9a2 Gja1 Vcam1 Genes from Table 6 Myog Fzd1 Pls2 FapSfrp1 Nes Cd9 Sfrp4 Oas1a Anxa8 Irf1 Lifr Ccna2 Epha2 Fyn Lipc Scyb9Serpine2 Ccnd2 Rasa3 Abcb3 Pdgfrb Ptpn12 Arhb Fap Casp6

[0363]

1 4 1 1716 DNA Homo sapiens CDS (119)..(1387) 1 cgcccagcga cgtgcgggcggcctggcccg cgccctcccg cgcccggcct gcgtcccgcg 60 ccctgcgcca ccgccgccgagccgcagccc gccgcgcgcc cccggcagcg ccggcccc 118 atg ccc gcc ggc cgc cggggc ccc gcc gcc caa tcc gcg cgg cgg ccg 166 Met Pro Ala Gly Arg Arg GlyPro Ala Ala Gln Ser Ala Arg Arg Pro 1 5 10 15 ccg ccg ttg ctg ccc ctgctg ctg ctg ctc tgc gtc ctc ggg gcg ccg 214 Pro Pro Leu Leu Pro Leu LeuLeu Leu Leu Cys Val Leu Gly Ala Pro 20 25 30 cga gcc gga tca gga gcc cacaca gct gtg atc agt ccc cag gat ccc 262 Arg Ala Gly Ser Gly Ala His ThrAla Val Ile Ser Pro Gln Asp Pro 35 40 45 acg ctt ctc atc ggc tcc tcc ctgctg gcc acc tgc tca gtg cac gga 310 Thr Leu Leu Ile Gly Ser Ser Leu LeuAla Thr Cys Ser Val His Gly 50 55 60 gac cca cca gga gcc acc gcc gag ggcctc tac tgg acc ctc aac ggg 358 Asp Pro Pro Gly Ala Thr Ala Glu Gly LeuTyr Trp Thr Leu Asn Gly 65 70 75 80 cgc cgc ctg ccc cct gag ctc tcc cgtgta ctc aac gcc tcc acc ttg 406 Arg Arg Leu Pro Pro Glu Leu Ser Arg ValLeu Asn Ala Ser Thr Leu 85 90 95 gct ctg gcc ctg gcc aac ctc aat ggg tccagg cag cgg tcg ggg gac 454 Ala Leu Ala Leu Ala Asn Leu Asn Gly Ser ArgGln Arg Ser Gly Asp 100 105 110 aac ctc gtg tgc cac gcc cgt gac ggc agcatc ctg gct ggc tcc tgc 502 Asn Leu Val Cys His Ala Arg Asp Gly Ser IleLeu Ala Gly Ser Cys 115 120 125 ctc tat gtt ggc ctg ccc cca gag aaa cccgtc aac atc agc tgc tgg 550 Leu Tyr Val Gly Leu Pro Pro Glu Lys Pro ValAsn Ile Ser Cys Trp 130 135 140 tcc aag aac atg aag gac ttg acc tgc cgctgg acg cca ggg gcc cac 598 Ser Lys Asn Met Lys Asp Leu Thr Cys Arg TrpThr Pro Gly Ala His 145 150 155 160 ggg gag acc ttc ctc cac acc aac tactcc ctc aag tac aag ctt agg 646 Gly Glu Thr Phe Leu His Thr Asn Tyr SerLeu Lys Tyr Lys Leu Arg 165 170 175 tgg tat ggc cag gac aac aca tgt gaggag tac cac aca gtg ggg ccc 694 Trp Tyr Gly Gln Asp Asn Thr Cys Glu GluTyr His Thr Val Gly Pro 180 185 190 cac tcc tgc cac atc ccc aag gac ctggct ctc ttt acg ccc tat gag 742 His Ser Cys His Ile Pro Lys Asp Leu AlaLeu Phe Thr Pro Tyr Glu 195 200 205 atc tgg gtg gag gcc acc aac cgc ctgggc tct gcc cgc tcc gat gta 790 Ile Trp Val Glu Ala Thr Asn Arg Leu GlySer Ala Arg Ser Asp Val 210 215 220 ctc acg ctg gat atc ctg gat gtg gtgacc acg gac ccc ccg ccc gac 838 Leu Thr Leu Asp Ile Leu Asp Val Val ThrThr Asp Pro Pro Pro Asp 225 230 235 240 gtg cac gtg agc cgc gtc ggg ggcctg gag gac cag ctg agc gtg cgc 886 Val His Val Ser Arg Val Gly Gly LeuGlu Asp Gln Leu Ser Val Arg 245 250 255 tgg gtg tcg cca ccc gcc ctc aaggat ttc ctc ttt caa gcc aaa tac 934 Trp Val Ser Pro Pro Ala Leu Lys AspPhe Leu Phe Gln Ala Lys Tyr 260 265 270 cag atc cgc tac cga gtg gag gacagt gtg gac tgg aag gtg gtg gac 982 Gln Ile Arg Tyr Arg Val Glu Asp SerVal Asp Trp Lys Val Val Asp 275 280 285 gat gtg agc aac cag acc tcc tgccgc ctg gcc ggc ctg aaa ccc ggc 1030 Asp Val Ser Asn Gln Thr Ser Cys ArgLeu Ala Gly Leu Lys Pro Gly 290 295 300 acc gtg tac ttc gtg caa gtg cgctgc aac ccc ttt ggc atc tat ggc 1078 Thr Val Tyr Phe Val Gln Val Arg CysAsn Pro Phe Gly Ile Tyr Gly 305 310 315 320 tcc aag aaa gcc ggg atc tggagt gag tgg agc cac ccc aca gcc gcc 1126 Ser Lys Lys Ala Gly Ile Trp SerGlu Trp Ser His Pro Thr Ala Ala 325 330 335 tcc act ccc cgc agt gag cgcccg ggc ccg ggc ggc ggg gcg tgc gaa 1174 Ser Thr Pro Arg Ser Glu Arg ProGly Pro Gly Gly Gly Ala Cys Glu 340 345 350 ccg cgg ggc gga gag ccg agctcg ggg ccg gtg cgg cgc gag ctc aag 1222 Pro Arg Gly Gly Glu Pro Ser SerGly Pro Val Arg Arg Glu Leu Lys 355 360 365 cag ttc ctg ggc tgg ctc aagaag cac gcg tac tgc tcc aac ctc agc 1270 Gln Phe Leu Gly Trp Leu Lys LysHis Ala Tyr Cys Ser Asn Leu Ser 370 375 380 ttc cgc ctc tac gac cag tggcga gcc tgg atg cag aag tcg cac aag 1318 Phe Arg Leu Tyr Asp Gln Trp ArgAla Trp Met Gln Lys Ser His Lys 385 390 395 400 acc cgc aac cag gac gagggg atc ctg ccc tcg ggc aga cgg ggc acg 1366 Thr Arg Asn Gln Asp Glu GlyIle Leu Pro Ser Gly Arg Arg Gly Thr 405 410 415 gcg aga ggt cct gcc agataa gctgtagggg ctcaggccac cctccctgcc 1417 Ala Arg Gly Pro Ala Arg 420acgtggagac gcagaggccg aacccaaact ggggccacct ctgtaccctc acttcagggc 1477acctgagcca ccctcagcag gagctggggt ggcccctgag ctccaacggc cataacagct 1537ctgactccca cgtgaggcca cctttgggtg caccccagtg ggtgtgtgtg tgtgtgtgag 1597ggttggttga gttgcctaga acccctgcca gggctggggg tgagaagggg agtcattact 1657ccccattacc tagggcccct ccaaaagagt ccttttaaat aaatgagcta tttaggtgc 1716 2422 PRT Homo sapiens 2 Met Pro Ala Gly Arg Arg Gly Pro Ala Ala Gln SerAla Arg Arg Pro 1 5 10 15 Pro Pro Leu Leu Pro Leu Leu Leu Leu Leu CysVal Leu Gly Ala Pro 20 25 30 Arg Ala Gly Ser Gly Ala His Thr Ala Val IleSer Pro Gln Asp Pro 35 40 45 Thr Leu Leu Ile Gly Ser Ser Leu Leu Ala ThrCys Ser Val His Gly 50 55 60 Asp Pro Pro Gly Ala Thr Ala Glu Gly Leu TyrTrp Thr Leu Asn Gly 65 70 75 80 Arg Arg Leu Pro Pro Glu Leu Ser Arg ValLeu Asn Ala Ser Thr Leu 85 90 95 Ala Leu Ala Leu Ala Asn Leu Asn Gly SerArg Gln Arg Ser Gly Asp 100 105 110 Asn Leu Val Cys His Ala Arg Asp GlySer Ile Leu Ala Gly Ser Cys 115 120 125 Leu Tyr Val Gly Leu Pro Pro GluLys Pro Val Asn Ile Ser Cys Trp 130 135 140 Ser Lys Asn Met Lys Asp LeuThr Cys Arg Trp Thr Pro Gly Ala His 145 150 155 160 Gly Glu Thr Phe LeuHis Thr Asn Tyr Ser Leu Lys Tyr Lys Leu Arg 165 170 175 Trp Tyr Gly GlnAsp Asn Thr Cys Glu Glu Tyr His Thr Val Gly Pro 180 185 190 His Ser CysHis Ile Pro Lys Asp Leu Ala Leu Phe Thr Pro Tyr Glu 195 200 205 Ile TrpVal Glu Ala Thr Asn Arg Leu Gly Ser Ala Arg Ser Asp Val 210 215 220 LeuThr Leu Asp Ile Leu Asp Val Val Thr Thr Asp Pro Pro Pro Asp 225 230 235240 Val His Val Ser Arg Val Gly Gly Leu Glu Asp Gln Leu Ser Val Arg 245250 255 Trp Val Ser Pro Pro Ala Leu Lys Asp Phe Leu Phe Gln Ala Lys Tyr260 265 270 Gln Ile Arg Tyr Arg Val Glu Asp Ser Val Asp Trp Lys Val ValAsp 275 280 285 Asp Val Ser Asn Gln Thr Ser Cys Arg Leu Ala Gly Leu LysPro Gly 290 295 300 Thr Val Tyr Phe Val Gln Val Arg Cys Asn Pro Phe GlyIle Tyr Gly 305 310 315 320 Ser Lys Lys Ala Gly Ile Trp Ser Glu Trp SerHis Pro Thr Ala Ala 325 330 335 Ser Thr Pro Arg Ser Glu Arg Pro Gly ProGly Gly Gly Ala Cys Glu 340 345 350 Pro Arg Gly Gly Glu Pro Ser Ser GlyPro Val Arg Arg Glu Leu Lys 355 360 365 Gln Phe Leu Gly Trp Leu Lys LysHis Ala Tyr Cys Ser Asn Leu Ser 370 375 380 Phe Arg Leu Tyr Asp Gln TrpArg Ala Trp Met Gln Lys Ser His Lys 385 390 395 400 Thr Arg Asn Gln AspGlu Gly Ile Leu Pro Ser Gly Arg Arg Gly Thr 405 410 415 Ala Arg Gly ProAla Arg 420 3 1246 DNA Homo sapiens CDS (39)..(1211) 3 ctgccccatgcagccctgag ccccacagca agtctgcc atg ggc cgc ggg gcc cgt 56 Met Gly ArgGly Ala Arg 1 5 gtc ccc tcg gag gcc ccg ggg gca ggc gtc gag cgc cgc tggctt gga 104 Val Pro Ser Glu Ala Pro Gly Ala Gly Val Glu Arg Arg Trp LeuGly 10 15 20 gcc gcg ctg gtc gcc ctg tgc ctc ctc ccc gcg ctg gtg ctg ctggcc 152 Ala Ala Leu Val Ala Leu Cys Leu Leu Pro Ala Leu Val Leu Leu Ala25 30 35 cgg ctg ggg gcc ccg gcg gtg ccg gcc tgg agc gca gcg cag gga gac200 Arg Leu Gly Ala Pro Ala Val Pro Ala Trp Ser Ala Ala Gln Gly Asp 4045 50 gtc gct gcg ctg ggc ctc tcg gcg gtc ccc ccc acc cgg gtc ccg ggc248 Val Ala Ala Leu Gly Leu Ser Ala Val Pro Pro Thr Arg Val Pro Gly 5560 65 70 cca ctg gcc ccc cgc aga cgc cgc tac acg ctg act cca gcc agg ctg296 Pro Leu Ala Pro Arg Arg Arg Arg Tyr Thr Leu Thr Pro Ala Arg Leu 7580 85 cgc tgg gac cac ttc aac ctc acc tac agg atc ctc tcc ttc ccg cgg344 Arg Trp Asp His Phe Asn Leu Thr Tyr Arg Ile Leu Ser Phe Pro Arg 9095 100 aac ctg ctg agc ccg cgg gag acg cgg cgg gcc cta gct gcc gcc ttc392 Asn Leu Leu Ser Pro Arg Glu Thr Arg Arg Ala Leu Ala Ala Ala Phe 105110 115 cgc atg tgg agc gac gtg tcc ccc ttc agc ttc cgc gag gtg gcc ccc440 Arg Met Trp Ser Asp Val Ser Pro Phe Ser Phe Arg Glu Val Ala Pro 120125 130 gag cag ccc agc gac ctc cgg ata ggc ttc tac ccg atc aac cac acg488 Glu Gln Pro Ser Asp Leu Arg Ile Gly Phe Tyr Pro Ile Asn His Thr 135140 145 150 gac tgc ctg gtc tcc gcg ctg cac cac tgc ttc gac ggc ccc acgggg 536 Asp Cys Leu Val Ser Ala Leu His His Cys Phe Asp Gly Pro Thr Gly155 160 165 gag ctg gcc cac gcc ttc ttc ccc ccg cac ggc ggc atc cac ttcgac 584 Glu Leu Ala His Ala Phe Phe Pro Pro His Gly Gly Ile His Phe Asp170 175 180 gac agc gag tac tgg gtc ctg ggc ccc acg cgc tac agc tgg aagaaa 632 Asp Ser Glu Tyr Trp Val Leu Gly Pro Thr Arg Tyr Ser Trp Lys Lys185 190 195 ggc gtg tgg ctc acg gac ctg gtg cac gtg gcg gcc cac gag atcggc 680 Gly Val Trp Leu Thr Asp Leu Val His Val Ala Ala His Glu Ile Gly200 205 210 cac gcg ctg ggc ctg atg cac tca caa cac ggc cgg gcg ctc atgcac 728 His Ala Leu Gly Leu Met His Ser Gln His Gly Arg Ala Leu Met His215 220 225 230 ctg aac gcc acg ctg cgc ggc tgg aag gcg ttg tcc cag gacgag ctg 776 Leu Asn Ala Thr Leu Arg Gly Trp Lys Ala Leu Ser Gln Asp GluLeu 235 240 245 tgg ggg ctg cac cgg ctc tac gga tgc ctc gac agg ctg ttcgtg tgc 824 Trp Gly Leu His Arg Leu Tyr Gly Cys Leu Asp Arg Leu Phe ValCys 250 255 260 gcg tcc tgg gcg cgg agg ggc ttc tgc gac gct cgc cgg cggctc atg 872 Ala Ser Trp Ala Arg Arg Gly Phe Cys Asp Ala Arg Arg Arg LeuMet 265 270 275 aag agg ctc tgc ccc agc agc tgc gac ttc tgc tac gaa ttcccc ttc 920 Lys Arg Leu Cys Pro Ser Ser Cys Asp Phe Cys Tyr Glu Phe ProPhe 280 285 290 ccc acg gtg gcc acc acc cca ccg ccc ccc agg acc aaa accagg ctg 968 Pro Thr Val Ala Thr Thr Pro Pro Pro Pro Arg Thr Lys Thr ArgLeu 295 300 305 310 gtg ccc gag ggc agg aac gtg acc ttc cgc tgc ggc cagaag atc ctc 1016 Val Pro Glu Gly Arg Asn Val Thr Phe Arg Cys Gly Gln LysIle Leu 315 320 325 cac aag aaa ggg aaa gtg tac tgg tac aag gac cag gagccc ctg gag 1064 His Lys Lys Gly Lys Val Tyr Trp Tyr Lys Asp Gln Glu ProLeu Glu 330 335 340 ttc tcc tac ccc ggc tac ctg gcc ctg ggc gag gcg cacctg agc atc 1112 Phe Ser Tyr Pro Gly Tyr Leu Ala Leu Gly Glu Ala His LeuSer Ile 345 350 355 atc gcc aac gcc gtc aat gag ggc acc tac acc tgc gtggtg cgc cgc 1160 Ile Ala Asn Ala Val Asn Glu Gly Thr Tyr Thr Cys Val ValArg Arg 360 365 370 cag cag cgc gtg ctg acc acc tac tcc tgg cga gtc cgtgtg cgg ggc 1208 Gln Gln Arg Val Leu Thr Thr Tyr Ser Trp Arg Val Arg ValArg Gly 375 380 385 390 tga gcccggctga taaagcactt tctctctgaa aaaaa 12464 390 PRT Homo sapiens 4 Met Gly Arg Gly Ala Arg Val Pro Ser Glu Ala ProGly Ala Gly Val 1 5 10 15 Glu Arg Arg Trp Leu Gly Ala Ala Leu Val AlaLeu Cys Leu Leu Pro 20 25 30 Ala Leu Val Leu Leu Ala Arg Leu Gly Ala ProAla Val Pro Ala Trp 35 40 45 Ser Ala Ala Gln Gly Asp Val Ala Ala Leu GlyLeu Ser Ala Val Pro 50 55 60 Pro Thr Arg Val Pro Gly Pro Leu Ala Pro ArgArg Arg Arg Tyr Thr 65 70 75 80 Leu Thr Pro Ala Arg Leu Arg Trp Asp HisPhe Asn Leu Thr Tyr Arg 85 90 95 Ile Leu Ser Phe Pro Arg Asn Leu Leu SerPro Arg Glu Thr Arg Arg 100 105 110 Ala Leu Ala Ala Ala Phe Arg Met TrpSer Asp Val Ser Pro Phe Ser 115 120 125 Phe Arg Glu Val Ala Pro Glu GlnPro Ser Asp Leu Arg Ile Gly Phe 130 135 140 Tyr Pro Ile Asn His Thr AspCys Leu Val Ser Ala Leu His His Cys 145 150 155 160 Phe Asp Gly Pro ThrGly Glu Leu Ala His Ala Phe Phe Pro Pro His 165 170 175 Gly Gly Ile HisPhe Asp Asp Ser Glu Tyr Trp Val Leu Gly Pro Thr 180 185 190 Arg Tyr SerTrp Lys Lys Gly Val Trp Leu Thr Asp Leu Val His Val 195 200 205 Ala AlaHis Glu Ile Gly His Ala Leu Gly Leu Met His Ser Gln His 210 215 220 GlyArg Ala Leu Met His Leu Asn Ala Thr Leu Arg Gly Trp Lys Ala 225 230 235240 Leu Ser Gln Asp Glu Leu Trp Gly Leu His Arg Leu Tyr Gly Cys Leu 245250 255 Asp Arg Leu Phe Val Cys Ala Ser Trp Ala Arg Arg Gly Phe Cys Asp260 265 270 Ala Arg Arg Arg Leu Met Lys Arg Leu Cys Pro Ser Ser Cys AspPhe 275 280 285 Cys Tyr Glu Phe Pro Phe Pro Thr Val Ala Thr Thr Pro ProPro Pro 290 295 300 Arg Thr Lys Thr Arg Leu Val Pro Glu Gly Arg Asn ValThr Phe Arg 305 310 315 320 Cys Gly Gln Lys Ile Leu His Lys Lys Gly LysVal Tyr Trp Tyr Lys 325 330 335 Asp Gln Glu Pro Leu Glu Phe Ser Tyr ProGly Tyr Leu Ala Leu Gly 340 345 350 Glu Ala His Leu Ser Ile Ile Ala AsnAla Val Asn Glu Gly Thr Tyr 355 360 365 Thr Cys Val Val Arg Arg Gln GlnArg Val Leu Thr Thr Tyr Ser Trp 370 375 380 Arg Val Arg Val Arg Gly 385390

1. A computer-readable medium comprising a plurality of digitallyencoded values representing the levels of expression of a plurality ofgenes listed in Table 1, 2, 5, 6 and/or 7 during bone or cartilageformation.
 2. The computer-readable medium of claim 1, comprising valuesrepresenting levels of expression of at least 5 genes listed in Table 1,2, 5, 6 and/or 7 during bone or cartilage formation.
 3. Thecomputer-readable medium of claim 1, comprising values representinglevels of expression of CLF-1 and MMP23 during bone or cartilageformation.
 4. The computer-readable medium of claim 1, comprising valuesrepresenting levels of expression of a plurality of genes listed inTable
 6. 5. The computer-readable medium of claim 1, further comprisingat least one value representing a level of expression of at least onegene that is up-or down-regulated during bone or cartilage formation ina precursor cell.
 6. The computer-readable medium of claim 1, comprisingat least one value representing a level of expression of at least onegene that is up-or down-regulated during a particular stage of bone orcartilage formation.
 7. The computer-readable medium of claim 6,comprising values representing levels of expression of at least one ofCyr61, Col2a1, Runx2, and Ctsk during bone or cartilage formation. 8.The computer-readable medium of claim 6, comprising values representinglevels of expression of a plurality of genes listed in Table
 7. 9. Thecomputer-readable medium of claim 1, comprising at least one valuerepresenting a level of expression of at least one gene that isco-regulated or functionally connected with a gene that is up-ordown-regulated during a particular stage of bone or cartilage formation.10. The computer-readable medium of claim 1, wherein the valuesrepresent ratios of, or differences between, a level of expression of agene in one sample and the level of expression of the gene in anothersample.
 11. The computer-readable medium of claim 1, wherein less thanabout 50% of the values represent expression levels of genes which arenot listed in Table 1, 2, 5, 6 and/or
 7. 12. A computer system,comprising: a database comprising values representing expression levelsof a plurality of genes listed in Table 1, 2, 5, 6 and/or 7 during boneor cartilage formation; and, a processor having instructions to, receiveat least one query value representing at least one level of expressionof at least one gene listed in Table 1, 2, 5, 6 and/or 7; and, comparethe at least one query value and the at least one database value. 12.The computer system of claim 8, wherein the query value represents thelevel of expression of a gene listed in Table 1, 2, 5, 6 and/or 7 in adiseased cell of a subject having or susceptible of having a diseaseselected from the group consisting of osteodystrophy, osteohypertrophy,osteoblastoma, osteopertrusis, osteogenesis imperfecta, osteoporosis,osteopenia, osteoma and osteoblastoma; periondontal disease;hyperparathyroidism; hypercalcemia of malignancy; Paget's disease;osteolytic lesions produced by bone metastasis; bone loss due toimmobilization or sex hormone deficiency; bone and cartilage loss causedby an inflammatory disease, rheumatoid arthritis, osteoarthritis andbone fractures.
 13. The computer system of claim 8, wherein the queryvalue represents the level of expression of a gene listed in Table 1, 2,5, 6 and/or 7 in a precursor cell for which the stage of bone orcartilage formation is unknown.
 12. A computer program for analyzinglevels of expression of a plurality of genes listed in Table 1, 2, 5, 6and/or 7 in a cell, the computer program being disposed on a computerreadable medium and including instructions for causing a processor to:receive query values representing levels of expression of a plurality ofgenes listed in Table 1, 2, 5, 6 and/or 7 in a query cell, and, comparethe query values with levels of expression of the plurality of geneslisted in Table 1, 2, 5, 6 and/or 7 in a reference cell.
 13. Acomposition comprising a plurality of detection agents of genes listedin Table 1, 2, 5, 6 and/or 7, which detection agents are capable ofdetecting the expression of the genes or the polypeptides encoded by thegenes, and wherein less than about 50% of the detection agents are ofgenes which are not listed in Table 1, 2, 5, 6 and/or
 7. 14. Thecomposition of claim 13, comprising detection agents of CLF-1 or MMP23.15. The composition of claim 13, wherein the detection agents areisolated nucleic acids that hybridize specifically to nucleic acidscorresponding to the genes.
 16. The composition of claim 14, comprisingisolated nucleic acids that hybridize specifically to at least fivegenes of Table
 6. 17. The composition of claim 13, comprising detectionagents of Cyr61, Col2a1, Runx2, or Ctsk.
 18. The composition of claim17, comprising detection agents of genes having expression profilessimilar to Cyr61, Col2a1, Runx2, or Ctsk.
 19. The composition of claim13, comprising isolated nucleic acids that hybridize specifically to atleast 10 different genes listed in Table 1, 2, 5, 6 and/or
 7. 20. Thecomposition of claim 19, comprising isolated nucleic acids thathybridize specifically to at least 100 different genes listed in Table1, 2, 5, 6 and/or
 7. 21. A solid surface to which are linked a pluralityof detection agents of genes which are listed in Table 1, 2, 5, 6 and/or7, which detection agents are capable of detecting the expression ofthegenes or the polypeptides encoded by the genes, and wherein less thanabout 50% of the detection agents are not detecting genes listed inTable 1, 2, 5, 6 and/or
 7. 22. The solid surface of claim 21, whereinthe detection agents are isolated nucleic acids that hybridizespecifically to the genes.
 23. The solid surface of claim 22, whereinthe detection agents are covalently linked to the solid surface.
 24. Acomposition comprising a plurality of antagonists of a plurality ofgenes listed in Table 1, 2, 5, 6 and/or
 7. 25. The composition of claim24, wherein the antagonists are antisense nucleic acids, siRNAs,ribozymes or dominant negative mutants.
 26. A composition comprising aplurality of agonists of a plurality of genes listed in Table 1, 2, 5, 6and/or
 7. 27. A method for determining the difference between levels ofexpression of a plurality of genes in Table 1, 2, 5, 6 and/or 7 in acell and reference levels of expression of the genes, comprisingproviding RNA from the cell; determining levels of RNA of a plurality ofgenes listed in Table 1, 2, 5, 6 and/or 7 to obtain the levels ofexpression of the plurality of genes in the cell; and comparing thelevels of expression of the plurality of genes in the cell to a set ofreference levels of expression of the genes, to thereby determine thedifference between levels of expression of the plurality of genes listedin Table 1, 2, 5, 6 and/or 7 in the cell and reference levels ofexpression of the genes.
 28. The method of claim 27, wherein the set ofreference levels of expression includes the levels of expression of thegenes during bone or cartilage formation.
 29. The method of claim 27,wherein the set of reference levels of expression includes the levels ofexpression of the genes during a particular stage of bone or cartilageformation.
 30. The method of claim 23, wherein the set of referencelevels of expression further includes the levels of expression of thegenes in a precursor cell.
 31. The method of claim 30, wherein the cellis a cell of a subject having or susceptible of having a diseaseselected from the group consisting of osteodystrophy, osteohypertrophy,osteoblastoma, osteopertrusis, osteogenesis imperfecta, osteoporosis,osteopenia, osteoma and osteoblastoma; periondontal disease;hyperparathyroidism; hypercalcemia of malignancy; Paget's disease;osteolytic lesions produced by bone metastasis; bone loss due toimmobilization or sex hormone deficiency; bone and cartilage loss causedby an inflammatory disease, rheumatoid arthritis, osteoarthritis andbone fractures.
 32. The method of claim 27, comprising incubating anucleic acid sample deuived from the RNA of the cell of the subject withnucleic acids corresponding to the genes, under conditions wherein twocomplementary nucleic acids hybridize to each other.
 33. The method ofclaim 32, wherein the nucleic acids corresponding to the genes areattached to a solid surface.
 34. The method of claim 27, comprisingentering the levels of expression of the plurality of genes into acomputer which comprises a memory with values representing the set ofreference levels of expression.
 35. The method of claim 34, whereincomparing the level comprises providing to the computer instructions toperform.
 36. A method for determining whether a subject has or is likelyto develop a disease related to bone or cartilage resorption, comprisingobtaining a biological sample from the subject and comparing geneexpression levels in the biological sample to those of a set ofreference levels of expression during normal bone and cartilageformation, wherein significant differences in the levels of expressionof the plurality of genes indicates that the subject has or is likely todevelop a disease related to bone or cartilage resorption.
 37. Themethod of claim 36, wherein the disease is selected from the groupconsisting of osteoporosis, osteopenia, periondontal disease; osteolyticlesions produced by bone metastasis; bone loss due to immobilization orsex hormone deficiency; bone and cartilage loss caused by aninflammatory disease, rheumatoid arthritis and osteoarthritis.
 38. Amethod for determining whether a subject has or is likely to develop adisease related to bone or cartilage formation, comprising obtaining abiological sample from the subject and comparing gene expression levelsin the biological sample to those of a set of reference levels ofexpression during normal bone and cartilage formation, whereinsignificant similarities in the levels of expression of the plurality ofgenes indicates that the subject has or is likely to develop a diseaserelated to bone or cartilage formation.
 39. The method of claim 38,wherein the disease is selected from the group consisting ofosteodystrophy, osteohypertrophy, osteoblastoma, osteopertrusis,osteogenesis imperfecta, osteoma and osteoblastoma, hyperparathyroidism;hypercalcemia of malignancy; and Paget's disease.
 40. A method fordetermining the effectiveness of a treatment intended to stimulate boneor cartilage formation, comprising obtaining a biological sample fromthe subject and comparing gene expression levels in the biologicalsample to those of a set of reference levels of expression during normalbone and cartilage formation, wherein significant similarities in thelevels of expression of the plurality of genes indicates that thetreatment is effective.
 41. The method of claim 40, wherein thebiological sample is obtained from the healing region of a bone fractureand a similarity in levels of expression of the plurality of genes inthe cell of the subject and the reference levels of expression indicatesthat the fracture is healing.
 42. The method of claim 40, furthercomprising iteratively providing a biological sample from the subject,such as to determine an evolution of the levels of expression of thegenes in the subject.
 43. The method of claim 40, wherein the set ofreference levels of expression is in the form of a database.
 40. Themethod of claim 43, wherein the database is included in acomputer-readable medium.
 41. The method of claim 40, wherein thedatabase is in communications with a microprocessor and microprocessorinstructions for providing a user interface to receive expression leveldata of a subject and to compare the expression level data with thedatabase.
 42. A method for determining the effectiveness of a treatmentintended to reduce bone or cartilage formation, comprising obtaining abiological sample from the subject and comparing gene expression levelsin the biological sample to those of a set of reference levels ofexpression during normal bone and cartilage formation, whereinsignificant differences in the levels of expression of the plurality ofgenes indicates that the treatment is effective.
 43. The method of claim36, comprising obtaining a sample; identifying expression levels of aplurality of genes listed in Table 1, 2, 5, 6 and/or 7 from said sample;determining whether the levels of expression of the genes in said sampleare more similar to those of a cell differentiating into bone orcartilage or to those of a precursor cell; and transmitting the results.44. The method of claim 43, wherein the results are transmitted across anetwork.
 45. A method for identifying a compound for treating a diseaserelated to bone or cartilage formation, comprising providing levels ofexpression of a plurality of genes listed in Table 1, 2, 5, 6 and/or 7in a cell of a subject incubated with a test compound; providing levelsof expression of a cell differentiating into bone or cartilage; andcomparing the two levels of expression, wherein significantly differentlevels of expression in the two cells indicates that the compound islikely to be effective for treating a disease related to bone orcartilage formation.
 46. A method for identifying a compound fortreating a disease related to bone or cartilage resorption, comprisingproviding levels of expression of a plurality of genes listed in Table1, 2, 5, 6 and/or 7 in a cell of a subject incubated with a testcompound; providing levels of expression of a cell differentiating intobone or cartilage; and comparing the two levels of expression, whereinsignificantly similar levels of expression in the two cells indicatesthat the compound is likely to be effective for treating a diseaserelated to bone or cartilage formation.
 47. A method for identifying acompound that modulates bone or cartilage formation, comprisingcontacting a precursor cell with an agent that stimulates bone orcartilage formation and a test compound; and determining the level ofexpression of one or more genes of Tables 1, 2, 6 and 7 during the boneor cartilage formation; wherein a significant similarity or differencebetween the expression level of the genes in the cell and referenceexpression levels of the genes during bone or cartilage formationindicates that the test compound modulates bone or cartilage formation.48. The method of claim 47, wherein the reference expression levels areessentially identical to the levels set forth in Table 1, 2, 5, 6 and/or7.
 49. A method for identifying a compound that stimulates bone orcartilage formation, comprising contacting a precursor cell with a testcompound; and determining the level of expression of one or more genesof Tables 1, 2, 6 and 7 in the cell over time; wherein a similaritybetween the expression level of the genes in the cell and referenceexpression levels of the genes during bone or cartilage formationindicates that the test compound stimulates bone or cartilage formation.50. The method of claim 49, wherein the reference expression levels arelevels set forth in Table 1, 2, 5, 6 and/or
 7. 51. A method foridentifying a compound that binds to a polypeptide encoded by a genelisted in Table 1, 2, 5, 6 and/or 7, comprising contacting a polypeptideencoded by a gene listed in Table 1, 2, 5, 6 and/or 7 with a testcompound under essentially physiological conditions; and determiningwhether the compound binds to the polypeptide;
 52. A method foridentifying a compound that modulates a biological activity of apolypeptide encoded by a gene listed in Table 1, 2, 5, 6 and/or 7,comprising contacting a polypeptide encoded by a gene listed in Table 1,2, 5, 6 and/or 7 with a test compound under essentially physiologicalconditions; and determining the biological activity of the polypeptide,wherein a higher or lower biological activity of the polypeptide in thepresence of the test compound relative to the absence of the testcompound indicates that the test compound modulates the biologicalactivity of the polypeptide.
 53. The method of claim 52, wherein thegene is CLF-1 or MMP23.
 54. A method for identifying a compound fortreating a disease related to bone or cartilage formation or resorption,comprising identifying a compound that modulates the activity of apolypeptide encoded by a gene listed in Table 1, 2, 5, 6 or 7 accordingto the method of claim 52; and contacting a precursor cell with thecompound in the presence or absence of an agent that stimulates thedifferentiation into bone or cartilage, wherein stimulation orinhibition of bone or cartilage formation from the cell indicates thatthe test compound is effective for treating a disease related to bone orcartilage formation or resorption.
 55. A method for treating a diseaserelated to bone or cartilage formation or resorption, comprisingadministering to a subject having a disease related to bone or cartilageformation or resorption a compound that modulates the biologicalactivity of a polypeptide encoded by a gene listed in Table 1, 2, 5, 6and/or 7 and thereby modulates bone or cartilage formation, to therebytreat the disease in the subject.
 56. A diagnostic or drug discoverykit, comprising a computer-readable medium of claim 1 and instructionsfor use.
 57. A diagnostic or drug discovery kit, comprising acomposition of claim 11 and instructions for use.
 58. A diagnostic ordrug discovery kit, comprising a solid surface of claim 17 andinstructions for use.